ASXL1

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Daichi Inoue - One of the best experts on this subject based on the ideXlab platform.

  • Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.
    Nature communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe, Akiho Tsuchiya
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

  • mutant ASXL1 induces age related expansion of phenotypic hematopoietic stem cells through activation of akt mtor pathway
    Nature Communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

  • 3011 mutant ASXL1 induces expansion of hematopoietic stem cells through activation of akt mtor pathway
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

  • 3011 – MUTANT ASXL1 INDUCES EXPANSION OF HEMATOPOIETIC STEM CELLS THROUGH ACTIVATION OF AKT/MTOR PATHWAY
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

  • Mutant ASXL1 Promotes Expansion of the Phenotypic Hematopoietic Stem Cell Compartment
    Blood, 2019
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Naru Sato, Hironobu Morinaga, Tomofusa Fukuyama
    Abstract:

    Somatic mutations of the ASXL1 gene are recurrently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations causes CH are not understood. Here, using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we investigated the effect of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). 　To examine the influence of ASXL1-MT on hematopoiesis, we bred the ASXL1-MT-KI mice with Vav-Cre transgenic mice. Young ASXL1-MT-KI mice (6-12 weeks) did not show significant changes in hematological parameters and differentiation status of peripheral blood. We observed the decreased frequency of hematopoietic stem and progenitor cells (HSPCs), including long-term HSCs (LT-HSCs). Competitive transplantation assays showed the reduced repopulation ability in ASXL1-MT-KI HSPCs. Thus, ASXL1-MT decreased the number and impaired the function of HSPCs in young mice. 　Next, we examined age-related changes in hematopoiesis caused by ASXL1-MT. Aged ASXL1-MT-KI mice displayed a myeloid-biased differentiation and hypocellular bone marrow, indicating the dysfunction of hematopoiesis. Interestingly, ASXL1-MT markedly increased the frequency of phenotypic LT-HSCs (pLT-HSCs) in aged mice (20-24 months). Competitive transplantation assays showed the impaired repopulation potential of pLT-HSCs from aged ASXL1-MT-KI mice. These data demonstrate that the increased pLT-HSCs in aged ASXL1-MT-KI mice are not functional HSCs with long-term repopulation potential. 　To elucidate how ASXL1-MT drives HSPC dysfunction, we conducted RNA-Seq analysis using HSPCs from young mice. This analysis revealed upregulation of mitochondrial genes in ASXL1-MT-KI HSPCs. In addition, MitoTracker staining, extracellular flux analyses and metabolome analyses demonstrated the enhanced mitochondrial metabolism in ASXL1-MT-KI HSPCs. We also found that the aberrantly elevated mitochondrial activity induced ROS overproduction and increased DNA damage, resulting in HSPC dysfunction. 　As a mechanism underlying the enhanced mitochondrial activity of ASXK1-MT-KI HSPCs, we revealed that ASXL1-MT activated the Akt/mTOR pathway in HSPCs. Treatment with an Akt inhibitor perifosine or an mTOR inhibitor rapamycin normalized the mitochondrial membrane potential and ROS levels in ASXL1-MT-KI HSPCs. Moreover, rapamycin treatment improved engraftment of ASXL1-MT-KI bone marrow cells after transplantation. These data indicate that the activated Akt/mTOR signaling leads to the enhanced mitochondrial activity, elevated ROS levels, and HSPC dysfunction in ASXL1-MT-KI mice. 　To assess the impact of the enhanced Akt/mTOR signaling on age-related changes in ASXL1-MT-KI mice, we administered rapamycin to aged ASXL1-MT-KI mice. Intriguingly, rapamycin treatment decreased the frequency of pLT-HSCs, and normalized the bone marrow cellularity in aged ASXL1-MT-KI mice. Cell cycle analysis revealed that pLT-HSCs in G0 phase were decreased in aged ASXL1-MT-KI mice, which was normalized by rapamycin treatment. These data demonstrate that the activated Akt/mTOR pathway provokes the aberrant expansion of pLT-HSCs in aged ASXL1-MT-KI mice. 　We next attempted to clarify the underlying mechanism of Akt activation in ASXL1-MT-KI mice. Immunoprecipitation experiments revealed that ASXL1-MT/BAP1 complex deubiquitinated AKT in 293T cells. To determine the role of endogenous Bap1 on Akt signaling, we assessed the effect of Bap1 deletion in murine bone marrow cells transformed by combined expression of SETBP1-D868N and ASXL1-MT (cSAM cells). A time course experiments showed Akt phosphorylation induced by IL-3 stimulation was attenuated and shortened in Bap1-depleted cSAM cells. These data suggest that ASXL1-MT/BAP1 complex deubiquitinate and stabilize phosphorylated Akt. 　In summary, we demonstrated that ASXL1-MT cooperated with BAP1 to promote AKT deubiquitination and activation. The activated Akt/mTOR pathway led to enhanced mitochondrial metabolism, elevated ROS levels and increased DNA damage. These molecular bases underlie the age-associated expansion of the pLT-HSC compartment. Our results underscore the possibility that CH can originate from a pLT-HSC with a limited repopulation potential. A pharmacological inhibition of the Akt/mTOR pathway could be a promising therapeutic intervention to individuals with CH harboring ASXL1 mutations. Disclosures No relevant conflicts of interest to declare.

Shuhei Asada - One of the best experts on this subject based on the ideXlab platform.

  • Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.
    Nature communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe, Akiho Tsuchiya
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

  • mutant ASXL1 induces age related expansion of phenotypic hematopoietic stem cells through activation of akt mtor pathway
    Nature Communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

  • HHEX promotes myeloid transformation in cooperation with mutant ASXL1
    Blood, 2020
    Co-Authors: Reina Takeda, Shuhei Asada, Y. Hayashi, Sung-joon Park, Akihiko Yokoyama, Hans Jiro Becker, Akinori Kanai, Valeria Visconte, Courtney E Hershberger, Taishi Yonezawa
    Abstract:

    Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified the hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT-expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and chromatin immunoprecipitation-next-generation sequencing analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicate that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells.

  • 3011 mutant ASXL1 induces expansion of hematopoietic stem cells through activation of akt mtor pathway
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

  • 3150 epigenetic regulator ASXL1 promotes paraspeckle formation through c terminal intrinsically disordered region in hematopoietic cells
    Experimental Hematology, 2020
    Co-Authors: Keita Yamamoto, Taishi Yonezawa, Shuhei Asada, Susumu Goyama, Tomofusa Fukuyama, Tsuyosho Fujino, Yousuke Tanaka, Toshio Kitamura
    Abstract:

    The importance of membraneless organelles and these formation mechanisms, liquid-liquid phase separation (LLPS) has recently gained large attention due to new understandings on their roles in cellular functions including transcription, RNA splicing and signal transduction. Paraspeckles are well-known membraneless organelless located in the interchromatin space of mammalian cell nuclei and consist of multiple proteins and RNAs, including NONO, SFPQ and NEAT1. These paraspeckle components are highly expressed in hematopoietic cells. However, their roles in hematopoiesis are largely unknown. In this study, we found an unexpected involvement of epigenetic regulator ASXL1 in paraspeckle formation in hematopoietic cells. ASXL1 has a long intrinsically disordered region (IDR) in its C-terminal region and forms phase-separated droplets in vitro. Of note, a large part of the IDR is located behind the mutational hotspot of ASXL1 gene, suggesting that most pathogenic ASXL1mutants lack IDR. Interestingly, the mutant ASXL1 (ASXL1-MT) lacking its C-terminal IDR could not form droplets efficiently. ASXL1 upregulates NEAT1 expression and increases NONO-NEAT1 interaction, while a pathogenic ASXL1-MT does not support the interaction among paraspeckle components. Consequently, we observed disruption of paraspeckles and aberrant localization of Nono in cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. We also showed that NONO depletion and forced expression of cytoplasmic NONO impair repopulating potential of HSPCs as ASXL1-MT does. The present findings highlight the potentially important role of paraspeckles in hematopoiesis and hematopoietic disorders.

Takeshi Fujino - One of the best experts on this subject based on the ideXlab platform.

  • Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.
    Nature communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe, Akiho Tsuchiya
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

  • mutant ASXL1 induces age related expansion of phenotypic hematopoietic stem cells through activation of akt mtor pathway
    Nature Communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

  • 3011 mutant ASXL1 induces expansion of hematopoietic stem cells through activation of akt mtor pathway
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

  • ASXL1 mutation in clonal hematopoiesis.
    Experimental hematology, 2020
    Co-Authors: Takeshi Fujino, Toshio Kitamura
    Abstract:

    Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a leading role in understanding the process of carcinogenesis. Clonal hematopoiesis (CH) with somatic mutations is observed in at least 10% of people over 65 years of age, without apparent hematologic disorders. CH is associated with increased risk of hematologic malignancies, which is indicative of a pre-malignant condition. Therefore, a better understanding of CH will help elucidate the mechanism of multi-step tumorigenesis in the hematopoietic system. Somatic mutations of ASXL1 are frequently detected in CH and myeloid malignancies. Although ASXL1 does not have any catalytic activity, it is involved in multiple histone modifications including H3K4me3, H3K27me3, and H2AK119Ub, suggesting its function as a scaffolding protein. Most ASXL1 mutations detected in CH and myeloid malignancies are frameshift or nonsense mutations of the last exon, generating a C-terminally truncated protein. Deletion of ASXL1 or expression of mutant ASXL1 in mice alters histone modifications and facilitates aberrant gene expression, resulting in myeloid transformation. On the contrary, these mice exhibit impaired functioning of hematopoietic stem cells (HSCs), suggesting the negative effects of ASXL1 mutations on stem cell function. Thus, how ASXL1 mutations induce a clonal advantage of hematopoietic cells and subsequent CH development has not been elucidated. Here, we have reviewed the current literature that enhances our understanding of ASXL1, including its mutational landscape, function, and involvement of its mutation in pathogenesis of CH and myeloid malignancies. Finally, we discuss the potential causes of CH harboring ASXL1 mutations with our latest knowledge.

  • 3011 – MUTANT ASXL1 INDUCES EXPANSION OF HEMATOPOIETIC STEM CELLS THROUGH ACTIVATION OF AKT/MTOR PATHWAY
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

Susumu Goyama - One of the best experts on this subject based on the ideXlab platform.

  • Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.
    Nature communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe, Akiho Tsuchiya
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

  • mutant ASXL1 induces age related expansion of phenotypic hematopoietic stem cells through activation of akt mtor pathway
    Nature Communications, 2021
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe
    Abstract:

    Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

  • 3011 mutant ASXL1 induces expansion of hematopoietic stem cells through activation of akt mtor pathway
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

  • 3150 epigenetic regulator ASXL1 promotes paraspeckle formation through c terminal intrinsically disordered region in hematopoietic cells
    Experimental Hematology, 2020
    Co-Authors: Keita Yamamoto, Taishi Yonezawa, Shuhei Asada, Susumu Goyama, Tomofusa Fukuyama, Tsuyosho Fujino, Yousuke Tanaka, Toshio Kitamura
    Abstract:

    The importance of membraneless organelles and these formation mechanisms, liquid-liquid phase separation (LLPS) has recently gained large attention due to new understandings on their roles in cellular functions including transcription, RNA splicing and signal transduction. Paraspeckles are well-known membraneless organelless located in the interchromatin space of mammalian cell nuclei and consist of multiple proteins and RNAs, including NONO, SFPQ and NEAT1. These paraspeckle components are highly expressed in hematopoietic cells. However, their roles in hematopoiesis are largely unknown. In this study, we found an unexpected involvement of epigenetic regulator ASXL1 in paraspeckle formation in hematopoietic cells. ASXL1 has a long intrinsically disordered region (IDR) in its C-terminal region and forms phase-separated droplets in vitro. Of note, a large part of the IDR is located behind the mutational hotspot of ASXL1 gene, suggesting that most pathogenic ASXL1mutants lack IDR. Interestingly, the mutant ASXL1 (ASXL1-MT) lacking its C-terminal IDR could not form droplets efficiently. ASXL1 upregulates NEAT1 expression and increases NONO-NEAT1 interaction, while a pathogenic ASXL1-MT does not support the interaction among paraspeckle components. Consequently, we observed disruption of paraspeckles and aberrant localization of Nono in cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. We also showed that NONO depletion and forced expression of cytoplasmic NONO impair repopulating potential of HSPCs as ASXL1-MT does. The present findings highlight the potentially important role of paraspeckles in hematopoiesis and hematopoietic disorders.

  • 3011 – MUTANT ASXL1 INDUCES EXPANSION OF HEMATOPOIETIC STEM CELLS THROUGH ACTIVATION OF AKT/MTOR PATHWAY
    Experimental Hematology, 2020
    Co-Authors: Takeshi Fujino, Daichi Inoue, Shiori Shikata, Shuhei Asada, Susumu Goyama, Yuki Sugiura, Satoshi Yamasaki, Akiko Matsumoto, Akiho Tsuchiya, Naru Sato
    Abstract:

    Epigenetic regulators, ASXL1, DNMT3A, and TET2 are frequently mutated in clonal hematopoiesis (CH). Dnmt3a- or Tet2-deficient mice increase self-renewal of hematopoietic stem cells (HSCs), suggesting that mutations in DNMT3A and TET2 provoke clonal expansion of hematopoietic cells, leading to subsequent CH in humans. On the contrary, ASXL1-mutated mice show reduced numbers and functions of HSCs. Thus, how ASXL1 mutations drive CH are not understood. Here, we investigated the effects of ASXL1 mutations on physiological aging of HSCs using knockin (KI) mice expressing a C-terminally truncated form of ASXL1 (ASXL1-MT). We found that HSCs expressing ASXL1-MT exhibited a competitive disadvantage after transplantation. On the other hand, in a genetic mosaic mouse, they displayed a growth advantage to occupy the HSC compartment over time, recapitulating CH in humans. As a mechanism by which ASXL1-MT causes CH, we show that ASXL1-MT binds and stabilizes phosphorylated Akt to activate Akt/mTOR pathway in coordination with Bap1. Activated Akt/mTOR induces dysregulated cell cycle progression and proliferation of HSCs. Meanwhile, it also compromises HSC functions along with activated mitochondrial metabolism, ROS overproduction, and increased DNA damage. Treatment with an mTOR inhibitor rapamycin suppressed aberrant proliferation of HSCs and ameliorated dysregulated hematopoiesis in aged ASXL1-MT KI mice. Taken together, ASXL1-MT impairs function of HSCs, whereas it confers a clonal advantage on HSCs during aging specifically in native hematopoiesis. ASXL1 mutation-mediated expansion of HSCs associated with increased DNA damage can induce development of CH, resulting in malignant transformation with secondary mutations. Akt/mTOR signaling could be a therapeutic target to individuals with CH harboring ASXL1 mutations.

Eun-joo Kim - One of the best experts on this subject based on the ideXlab platform.

  • ASXL1 ablation in mouse embryonic stem cells impairs neural differentiation without affecting self-renewal
    Biochemical and biophysical research communications, 2018
    Co-Authors: Ui Hyun Park, Seungtae Moon, Hyesook Youn, Jin-taek Hwang, Myengmo Kang, Eun-joo Kim
    Abstract:

    Additional sex comb-like1 (ASXL1) is known as a chromatin modulator that plays dual functions in transcriptional regulation depending on the cell type. Recent studies using ASXL1 knockout mice revealed that ASXL1 is important for the proliferation and differentiation of hematopoietic progenitor cells, and the development of organs. Although we previously reported ASXL1 as a Sox2 target gene, its function in embryonic stem cells (ESCs) remains largely unknown. For this purpose, we isolated ESCs from the blastocyst inner cell mass of ASXL1-/- mice. ASXL1 deficiency in ESCs exhibited no effect on cell proliferation, expression of core pluripotent transcription factors, or alkaline phosphatase activity, suggesting dispensability of ASXL1 for self-renewal of ESCs. By contrast, the differentiation of ASXL1-/- ESCs was significantly affected as shown by size reductions of embryoid bodies accompanied with apoptosis, aberrant expression of differentiation genes, downregulation of bivalent neurogenesis genes, and abnormal axon formation in neurons. Overall, our findings indicated that ASXL1 played a critical role in regulating genes associated with neural differentiation without affecting self-renewal of mouse ESCs.

  • ASXL1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation.
    Scientific reports, 2017
    Co-Authors: Hyesook Youn, Seungtae Moon, Ui Hyun Park, Tae-yoon Kim, Yong-kyu Lee, Jin-taek Hwang, Eun-joo Kim
    Abstract:

    Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation–associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in ASXL1-deficient mouse embryonic fibroblasts (MEFs). We found that ASXL1, through amino acids 371 to 655, interacts with the kinase domain of AKT1. In ASXL1-null MEFs, IGF-1 was unable to induce AKT1 phosphorylation and activation; p27Kip1, which forms a ternary complex with ASXL1 and AKT1, therefore remained unphosphorylated. Hypophosphorylated p27Kip1 is able to enter the nucleus, where it prevents the phosphorylation of Rb; this ultimately leads to the down-regulation of E2F target genes as confirmed by microarray analysis. We also found that senescence-associated (SA) genes were upregulated and that SA β-gal staining was increased in ASXL1 −/− MEFs. Further, the treatment of an AKT inhibitor not only stimulated nuclear accumulation of p27Kip1 leading to E2F inactivation, but also promoted senescence. Finally, ASXL1 disruption augmented the expression of p16Ink4a as result of the defect in ASXL1-Ezh2 cooperation. Overall, our study provides the first evidence that ASXL1 both activates the AKT-E2F pathway and cooperates with Ezh2 through direct interactions at early embryonic stages, reflecting that ASXL1 disruption causes cellular senescence.

  • Role of ASXL1 in kidney podocyte development via its interaction with Wtip
    Biochemical and biophysical research communications, 2015
    Co-Authors: Seungtae Moon, Eun-joo Kim
    Abstract:

    Additional sex comb-like (ASXL) family proteins are chromatin factors that function in transcriptional activation and repression. However, the underlying mechanisms and biological implications have not been well established. Here, we identified a LIM domain-containing protein, Wilms tumor 1-interacting protein (WTIP), as an ASXL1-binding partner. Biochemical assays confirmed an interaction between the murine homologs ASXL1 and Wtip. The suppressive role of Wtip in WT1 function and the expression of Wtip in kidney podocytes prompted us to investigate the role of ASXL1 in the kidney using ASXL1-null mice. In homozygous ASXL1(-/-) embryos, defects in kidney size and glomerular podocyte morphology were observed. Furthermore, up-regulation of Wt1/Wtip target genes was observed in the kidneys of ASXL1-null embryos. Overall, these findings implicate ASXL1 in the maintenance of podocyte structure via its association with Wtip and in the regulation of WT1 signaling during early kidney development.

  • Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis.
    Biochemical and biophysical research communications, 2013
    Co-Authors: Ui Hyun Park, Mi-ran Seong, Eun-joo Kim, Won Hee Hur, Sung Woo Kim, Seung Kew Yoon
    Abstract:

    Liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, plays a pivotal role in hepatic cholesterol and lipid metabolism, regulating the expression of genes associated with hepatic lipogenesis. The additional sex comb-like (ASXL) family was postulated to regulate chromatin function. Here, we investigate the roles of ASXL1 and ASXL2 in regulating LXRα activity. We found that ASXL1 suppressed ligand-induced LXRα transcriptional activity, whereas ASXL2 increased LXRα activity through direct interaction in the presence of the ligand. Chromatin immunoprecipitation (ChIP) assays showed ligand-dependent recruitment of ASXLs to ABCA1 promoters, like LXRα. Knockdown studies indicated that ASXL1 inhibits, while ASXL2 increases, lipid accumulation in H4IIE cells, similar to their roles in transcriptional regulation. We also found that ASXL1 expression increases under fasting conditions, and decreases in insulin-treated H4IIE cells and the livers of high-fat diet-fed mice. Overall, these results support the reciprocal role of the ASXL family in lipid homeostasis through the opposite regulation of LXRα.

  • ASXL1 Represses Retinoic Acid Receptor-mediated Transcription through Associating with HP1 and LSD1
    The Journal of biological chemistry, 2009
    Co-Authors: Sang-wang Lee, Ui Hyun Park, Myengmo Kang, Yang-sook Cho, Eun-joo Kim
    Abstract:

    We previously suggested that ASXL1 (additional sex comb-like 1) functions as either a coactivator or corepressor for the retinoid receptors retinoic acid receptor (RAR) and retinoid X receptor in a cell type-specific manner. Here, we provide clues toward the mechanism underlying ASXL1-mediated repression. Transfection assays in HEK293 or H1299 cells indicated that ASXL1 alone possessing autonomous transcriptional repression activity significantly represses RAR- or retinoid X receptor-dependent transcriptional activation, and the N-terminal portion of ASXL1 is responsible for the repression. Amino acid sequence analysis identified a consensus HP1 (heterochromatin protein 1)-binding site (HP1 box, PXVXL) in that region. Systematic in vitro and in vivo assays revealed that the HP1 box in ASXL1 is critical for the interaction with the chromoshadow domain of HP1. Transcription assays with HP1 box deletion or HP1α knockdown indicated that HP1α is required for ASXL1-mediated repression. Furthermore, we found a direct interaction of ASXL1 with histone H3 demethylase LSD1 through the N-terminal region nearby the HP1-binding site. ASXL1 binding to LSD1 was greatly increased by HP1α, resulting in the formation of a ternary complex. LSD1 cooperates with ASXL1 in transcriptional repression, presumably by removing H3K4 methylation, an active histone mark, but not H3K9 methylation, a repressive histone mark recognized by HP1. This possibility was supported by chromatin immunoprecipitation assays followed by ASXL1 overexpression or knockdown. Overall, this study provides the first evidence that ASXL1 cooperates with HP1 to modulate LSD1 activity, leading to a change in histone H3 methylation and thereby RAR repression.

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