The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Ling Zhao - One of the best experts on this subject based on the ideXlab platform.
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runx1 is strictly required for cbfb myh11 induced leukemia development
Blood, 2016Co-Authors: Tao Zhen, Ling Zhao, Erika Mijin Kwon, Katherine R Hyde, Guadalupe Lopez, Lemlem AlemuAbstract:Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. The prevailing hypothesis for the mechanism of leukemia development by CBFbeta-SMMHC, the fusion protein encoded by CBFB-MYH11, is that CBFbeta-SMMHC is a dominant negative repressor of RUNX1, a transcription factor that physically interacts with CBFbeta and CBFbeta-SMMHC. If this hypothesis is correct, reducing RUNX1 activity should facilitate Leukemogenesis by CBFB-MYH11. In fact, loss-of-function mutations in RUNX1 are common in human AML, but not in inv(16) AML. However, we previously demonstrated that CBFB-MYH11 has RUNX1-repression independent functions (Hyde et al., Blood 115:1433, 2010). Moreover, we recently showed that a dominant negative allele of Runx1, Runx1-lz, delayed Leukemogenesis by CBFB-MYH11 in a mouse model (Hyde et al., Leukemia 29:1771, 2015). These findings challenge the RUNX1-repression model for CBFbeta-SMMHC mediated Leukemogenesis. However, our previous findings are not conclusive since the Runx1+/lz mice used in the previous study have one wild-type Runx1 allele, and still retain some Runx1 function. To definitively address this question, we crossed Cre-based conditional Runx1 knockout mice (Runx1f/f) with Cre-based conditional Cbfb-MYH11 knockin mice (Cbfb+/56M) and Mx1-Cre mice to generate Runx1f/f, Mx1-Cre, Cbfb+/56Mmice, which express CBFbeta-SMMHC but not Runx1 after pIpC (poly I:C) treatment to induce Cre expression. Runx1f/f, Mx1-Cre, Cbfb+/56Mmice had more severe platelet deficiencies and higher numbers of Lin-/Sca1-/C-kit+ progenitors and Lin-/Sca1+/C-kit+ hematopoietic stem cells in the bone marrow when comapred with Runx1f/f, Mx1-Cre mice. Unexpectedly Runx1f/f, Mx1-Cre, Cbfb+/56Mmice also developed severe macrocytic anemia within two weeks after pIpC induction, which was lethal in about 1/3 of the mice. However, none of the Runx1f/f, Mx1-Cre, Cbfb+/56M mice developed leukemia up to one year after pIpC treatment. In contrast, all Mx1-Cre, Cbfb+/56M mice developed leukemia with an average survival of 4 months, as reported previously. These results suggest that Runx1 is strictly required for Cbfb-MYH11 induced Leukemogenesis. To further study the mechanism of Leukemogenesis, we performed RNA-Seq on C-kit+ bone marrow cells isolated from mice two weeks after pIpC treatment, to explore the global gene expression changes caused by Runx1 knockout on Cbfb-MYH11 expressing mice. Our preliminary data analysis showed that 1688 genes were differential expressed (Padj ≤0.05, FC ≥ 2) between Runx1f/f, Mx1-Cre, Cbfb+/56M and Mx1-Cre, Cbfb+/56M mice. Interestingly, many of these genes (48%) are Runx1 target genes. The above results suggest that mis-regulating the expression of Runx1 target genes contributes to Leukemogenesis by CBFbeta-SMMHC. Disclosures No relevant conflicts of interest to declare.
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runx1 is required for hematopoietic defects and Leukemogenesis in cbfb myh11 knock in mice
Leukemia, 2015Co-Authors: Lemlem Alemu, R K Hyde, Ling Zhao, L AlemuAbstract:Runx1 is required for hematopoietic defects and Leukemogenesis in Cbfb-MYH11 knock-in mice
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Abstract 3850: The interaction of RUNX1 with CBFβ-SMMHC during Leukemogenesis.
Tumor Biology, 2013Co-Authors: Ling Zhao, Lemlem Alemu, R. Katherine Hyde, Pu Paul LiuAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Chromosome 16 inversion is associated with acute myeloid leukemia subtype M4Eo and produces a fusion gene CBFB-MYH11 that contains part of the core binding factor (CBF) β gene CBFB, and part of the smooth muscle myosin heavy chain (SMMHC) gene MYH11. This fusion gene encodes a fusion protein CBFβ-SMMHC, which is oncogenic and binds to the runt domain (RD) of RUNX1, another member of the CBF transcription factor family, resulting in repression of RUNX1 transactivation. We have generated mouse models by conventional and conditional knock-in of the Cbfb-MYH11 fusion gene and demonstrated that Cbfb-MYH11 represses Runx1 function in hematopoiesis and predisposes mice to myeloid leukemia (Castilla et. al., Cell 1996; Nat Genet, 1999). RUNX1 binding and repression was previously considered a key step in Leukemogenesis by CBFβ-SMMHC. In order to dissect the molecular mechanism of RUNX1 and CBFβ-SMMHC interaction during Leukemogenesis, we generated a knock-in mouse model with deleted high affinity binding site of Cbfb-MYH11. We found accelerated leukemia development in these mice (Kamikubo et.al., Cancer cell, 2010) suggesting that Cbfb-MYH11 play an independent role apart from Runx1 binding and repression. To test if Runx1 is involved in the leukemia development and progression, we crossed Cbfb-MYH11 knock-in mice with mice harboring one of the two mutant alleles of Runx1 - Runx1+/- and Runx1+/Lzd. Runx1+/- contains a null allele while Runx1+/Lzd contains a knocked-in fusion between the RD of Runx1 and the LacZ gene, which is partially dominant-negative in reporter assays. We have determined the rate and percentage of leukemia development in these mice. We found that the Cbfb-MYH11 mice that were Runx1+/- had a similar rate of Leukemogenesis when compared with Cbfb-MYH11 mice that were Runx1+/+. However, the Cbfb-MYH11 mice that were Runx1+/Lzd had significantly delayed Leukemogenesis as compared to Cbfb-MYH11 mice that were Runx1+/+. Moreover, some of the Cbfb-MYH11; Runx1+/Lzd mice did not develop leukemia at the end of the one-year observation. We detected a decrease of BrdU incorporation in the bone marrow cells in mice with the Runx1+/Lzd allele, suggesting that the delayed leukemia development resulted, at least in part, from decreased proliferation. These data demonstrated that Runx1 is likely required for Leukemogenesis by CBFβ-SMMHC. Citation Format: Ling Zhao, R Katherine Hyde, Lemlem Alemu, P Paul Liu. The interaction of RUNX1 with CBFβ-SMMHC during Leukemogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3850. doi:10.1158/1538-7445.AM2013-3850
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cbfb runx1 repression independent blockage of differentiation and accumulation of csf2rb expressing cells by cbfb myh11
Blood, 2010Co-Authors: Yasuhiko Kamikubo, Martha Kirby, Lemlem Alemu, Stacie M. Anderson, Katherine R Hyde, Ling ZhaoAbstract:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates Leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for Leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression–independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11+ leukemia samples. Interestingly, Cbfb-MYH11+ preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb+. Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression–independent activities contribute to Leukemogenesis by Cbfb-MYH11.
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Cbfb/Runx1-repression independent blockage of differentiation and accumulation of Csf2rb expressing cells by Cbfb-MYH11
Blood, 2009Co-Authors: R. Katherine Hyde, Yasuhiko Kamikubo, Martha Kirby, Lemlem Alemu, Stacie M. Anderson, Ling ZhaoAbstract:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates Leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for Leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression–independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11+ leukemia samples. Interestingly, Cbfb-MYH11+ preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb+. Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression–independent activities contribute to Leukemogenesis by Cbfb-MYH11.
Lemlem Alemu - One of the best experts on this subject based on the ideXlab platform.
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runx1 is strictly required for cbfb myh11 induced leukemia development
Blood, 2016Co-Authors: Tao Zhen, Ling Zhao, Erika Mijin Kwon, Katherine R Hyde, Guadalupe Lopez, Lemlem AlemuAbstract:Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. The prevailing hypothesis for the mechanism of leukemia development by CBFbeta-SMMHC, the fusion protein encoded by CBFB-MYH11, is that CBFbeta-SMMHC is a dominant negative repressor of RUNX1, a transcription factor that physically interacts with CBFbeta and CBFbeta-SMMHC. If this hypothesis is correct, reducing RUNX1 activity should facilitate Leukemogenesis by CBFB-MYH11. In fact, loss-of-function mutations in RUNX1 are common in human AML, but not in inv(16) AML. However, we previously demonstrated that CBFB-MYH11 has RUNX1-repression independent functions (Hyde et al., Blood 115:1433, 2010). Moreover, we recently showed that a dominant negative allele of Runx1, Runx1-lz, delayed Leukemogenesis by CBFB-MYH11 in a mouse model (Hyde et al., Leukemia 29:1771, 2015). These findings challenge the RUNX1-repression model for CBFbeta-SMMHC mediated Leukemogenesis. However, our previous findings are not conclusive since the Runx1+/lz mice used in the previous study have one wild-type Runx1 allele, and still retain some Runx1 function. To definitively address this question, we crossed Cre-based conditional Runx1 knockout mice (Runx1f/f) with Cre-based conditional Cbfb-MYH11 knockin mice (Cbfb+/56M) and Mx1-Cre mice to generate Runx1f/f, Mx1-Cre, Cbfb+/56Mmice, which express CBFbeta-SMMHC but not Runx1 after pIpC (poly I:C) treatment to induce Cre expression. Runx1f/f, Mx1-Cre, Cbfb+/56Mmice had more severe platelet deficiencies and higher numbers of Lin-/Sca1-/C-kit+ progenitors and Lin-/Sca1+/C-kit+ hematopoietic stem cells in the bone marrow when comapred with Runx1f/f, Mx1-Cre mice. Unexpectedly Runx1f/f, Mx1-Cre, Cbfb+/56Mmice also developed severe macrocytic anemia within two weeks after pIpC induction, which was lethal in about 1/3 of the mice. However, none of the Runx1f/f, Mx1-Cre, Cbfb+/56M mice developed leukemia up to one year after pIpC treatment. In contrast, all Mx1-Cre, Cbfb+/56M mice developed leukemia with an average survival of 4 months, as reported previously. These results suggest that Runx1 is strictly required for Cbfb-MYH11 induced Leukemogenesis. To further study the mechanism of Leukemogenesis, we performed RNA-Seq on C-kit+ bone marrow cells isolated from mice two weeks after pIpC treatment, to explore the global gene expression changes caused by Runx1 knockout on Cbfb-MYH11 expressing mice. Our preliminary data analysis showed that 1688 genes were differential expressed (Padj ≤0.05, FC ≥ 2) between Runx1f/f, Mx1-Cre, Cbfb+/56M and Mx1-Cre, Cbfb+/56M mice. Interestingly, many of these genes (48%) are Runx1 target genes. The above results suggest that mis-regulating the expression of Runx1 target genes contributes to Leukemogenesis by CBFbeta-SMMHC. Disclosures No relevant conflicts of interest to declare.
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runx1 is required for hematopoietic defects and Leukemogenesis in cbfb myh11 knock in mice
Leukemia, 2015Co-Authors: Lemlem Alemu, R K Hyde, Ling Zhao, L AlemuAbstract:Runx1 is required for hematopoietic defects and Leukemogenesis in Cbfb-MYH11 knock-in mice
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Abstract 3850: The interaction of RUNX1 with CBFβ-SMMHC during Leukemogenesis.
Tumor Biology, 2013Co-Authors: Ling Zhao, Lemlem Alemu, R. Katherine Hyde, Pu Paul LiuAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Chromosome 16 inversion is associated with acute myeloid leukemia subtype M4Eo and produces a fusion gene CBFB-MYH11 that contains part of the core binding factor (CBF) β gene CBFB, and part of the smooth muscle myosin heavy chain (SMMHC) gene MYH11. This fusion gene encodes a fusion protein CBFβ-SMMHC, which is oncogenic and binds to the runt domain (RD) of RUNX1, another member of the CBF transcription factor family, resulting in repression of RUNX1 transactivation. We have generated mouse models by conventional and conditional knock-in of the Cbfb-MYH11 fusion gene and demonstrated that Cbfb-MYH11 represses Runx1 function in hematopoiesis and predisposes mice to myeloid leukemia (Castilla et. al., Cell 1996; Nat Genet, 1999). RUNX1 binding and repression was previously considered a key step in Leukemogenesis by CBFβ-SMMHC. In order to dissect the molecular mechanism of RUNX1 and CBFβ-SMMHC interaction during Leukemogenesis, we generated a knock-in mouse model with deleted high affinity binding site of Cbfb-MYH11. We found accelerated leukemia development in these mice (Kamikubo et.al., Cancer cell, 2010) suggesting that Cbfb-MYH11 play an independent role apart from Runx1 binding and repression. To test if Runx1 is involved in the leukemia development and progression, we crossed Cbfb-MYH11 knock-in mice with mice harboring one of the two mutant alleles of Runx1 - Runx1+/- and Runx1+/Lzd. Runx1+/- contains a null allele while Runx1+/Lzd contains a knocked-in fusion between the RD of Runx1 and the LacZ gene, which is partially dominant-negative in reporter assays. We have determined the rate and percentage of leukemia development in these mice. We found that the Cbfb-MYH11 mice that were Runx1+/- had a similar rate of Leukemogenesis when compared with Cbfb-MYH11 mice that were Runx1+/+. However, the Cbfb-MYH11 mice that were Runx1+/Lzd had significantly delayed Leukemogenesis as compared to Cbfb-MYH11 mice that were Runx1+/+. Moreover, some of the Cbfb-MYH11; Runx1+/Lzd mice did not develop leukemia at the end of the one-year observation. We detected a decrease of BrdU incorporation in the bone marrow cells in mice with the Runx1+/Lzd allele, suggesting that the delayed leukemia development resulted, at least in part, from decreased proliferation. These data demonstrated that Runx1 is likely required for Leukemogenesis by CBFβ-SMMHC. Citation Format: Ling Zhao, R Katherine Hyde, Lemlem Alemu, P Paul Liu. The interaction of RUNX1 with CBFβ-SMMHC during Leukemogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3850. doi:10.1158/1538-7445.AM2013-3850
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cbfb runx1 repression independent blockage of differentiation and accumulation of csf2rb expressing cells by cbfb myh11
Blood, 2010Co-Authors: Yasuhiko Kamikubo, Martha Kirby, Lemlem Alemu, Stacie M. Anderson, Katherine R Hyde, Ling ZhaoAbstract:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates Leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for Leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression–independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11+ leukemia samples. Interestingly, Cbfb-MYH11+ preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb+. Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression–independent activities contribute to Leukemogenesis by Cbfb-MYH11.
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Cbfb/Runx1-repression independent blockage of differentiation and accumulation of Csf2rb expressing cells by Cbfb-MYH11
Blood, 2009Co-Authors: R. Katherine Hyde, Yasuhiko Kamikubo, Martha Kirby, Lemlem Alemu, Stacie M. Anderson, Ling ZhaoAbstract:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates Leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for Leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression–independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11+ leukemia samples. Interestingly, Cbfb-MYH11+ preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb+. Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression–independent activities contribute to Leukemogenesis by Cbfb-MYH11.
R K Hyde - One of the best experts on this subject based on the ideXlab platform.
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runx1 is required for hematopoietic defects and Leukemogenesis in cbfb myh11 knock in mice
Leukemia, 2015Co-Authors: Lemlem Alemu, R K Hyde, Ling Zhao, L AlemuAbstract:Runx1 is required for hematopoietic defects and Leukemogenesis in Cbfb-MYH11 knock-in mice
Y Wang - One of the best experts on this subject based on the ideXlab platform.
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dysfunction of the wt1 meg3 signaling promotes aml Leukemogenesis via p53 dependent and independent pathways
Leukemia, 2017Co-Authors: Y Lyu, J Lou, Y Yang, J Feng, Y Hao, S Huang, L Yin, D Huang, D Zou, Y WangAbstract:Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses Leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms’ tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten–eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote Leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML Leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.
Hong-bing Shu - One of the best experts on this subject based on the ideXlab platform.
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MLL1/WDR5 complex in Leukemogenesis and epigenetic regulation.
Chinese journal of cancer, 2011Co-Authors: Hong-bing ShuAbstract:MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components. It plays important roles in developmental events, transcriptional regulation, and Leukemogenesis. MLL1 -fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia, which occurs in over 70% infant leukemia patients and often accompanies poor prognosis. Investigations in the past years on Leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.
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mll1 wdr5 complex in Leukemogenesis and epigenetic regulation
Chinese Journal of Cancer, 2011Co-Authors: Hong-bing ShuAbstract:MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components. It plays important roles in developmental events, transcriptional regulation, and Leukemogenesis. MLL1 -fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia, which occurs in over 70% infant leukemia patients and often accompanies poor prognosis. Investigations in the past years on Leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.
