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Jeffrey W. Taub - One of the best experts on this subject based on the ideXlab platform.

  • Overexpression of GATA1 Confers Resistance to Chemotherapy in Acute Megakaryocytic Leukemia
    PloS one, 2013
    Co-Authors: John Timothy Caldwell, Alan A Dombkowski, Steven Buck, Larry H. Matherly, Holly Edwards, Jeffrey W. Taub
    Abstract:

    It has been previously shown that Acute myeloid Leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with Acute Megakaryocytic Leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the Megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.

  • overexpression of gata1 confers chemotherapy resistance in pediatric Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Alan A Dombkowski, Mark Stout, Steven Buck, Larry H. Matherly, Chengzhi Xie, Maggie Keller, Jeffrey W. Taub
    Abstract:

    Abstract 2039 Poster Board II-16 Acute Megakaryocytic Leukemia (AMkL; M7) is a biologically heterogeneous form of AML, representing ∼10% of pediatric and 1-2% of adult AML cases. AMkL is the most common AML subtype of children with Down syndrome (DS). DS children with AMkL have an excellent prognosis with EFS rates of 80-100% when treated with ara-C/anthracycline-based protocols, in contrast to the Disclosures: No relevant conflicts of interest to declare.

  • runx1 regulates phosphoinositide 3 kinase akt pathway role in chemotherapy sensitivity in Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Jeffrey W. Taub, Alan A Dombkowski, Katherine M Lafiura, Steven Buck, Chengzhi Xie, Julie L Boerner, Larry H. Matherly
    Abstract:

    RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in Acute Leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in Acute Leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with Acute Megakaryocytic Leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antiLeukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

  • mutational spectrum at gata1 provides insights into mutagenesis and leukemogenesis in down syndrome
    Blood, 2009
    Co-Authors: Diane C Cabelof, Jeffrey W. Taub, Larry H. Matherly, Hiral Patel, Qing Chen, Holly Van Remmen
    Abstract:

    Down syndrome (DS) children have a unique genetic susceptibility to develop Leukemia, in particular, Acute Megakaryocytic Leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of Leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-β-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop Leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-β-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.

  • risk for Leukemia in infants without down syndrome who have transient myeloproliferative disorder
    The Journal of Pediatrics, 2006
    Co-Authors: Thomas Cushing, Carla S Wilson, Yubin Ge, Kaaren K Reichard, Carol L Clericuzio, Jeffrey W. Taub, Stuart S Winter
    Abstract:

    Transient myeloproliferative disorder (TMD) occurs in 10% of infants with Down syndrome (DS). Down syndrome infants with resolved TMD may later develop Acute Megakaryocytic Leukemia (AMKL). In these patients, AMKL is associated with somatic mutations in the X-linked transcription factor gene, GATA1 . AMKL also has been described after TMD in children without DS. We report on a non-DS child identified with trisomy 21 mosaicism and a GATA1 mutation in the original blast cells who has been followed for 2 years without exhibiting AMKL. Currently, the risk for such infants developing Acute Leukemia is uncertain. We recommend that nondysmorphic infants with TMD undergo chromosome analysis for trisomy 21 and testing for GATA1 mutations to aid surveillance for leukemic transformation.

Tsuneo Sasaki - One of the best experts on this subject based on the ideXlab platform.

  • a case of Acute Megakaryocytic Leukemia associated with a nonseminomatous primary mediastinal germ cell tumor diagnosed through elevation of serum lactate dehydrogenase
    International Journal of Case Reports and Images, 2015
    Co-Authors: Emi Noguchi, Yasushi Omuro, Yoshiharu Maeda, Tsuneo Sasaki
    Abstract:

    Introduction: Hematologic malignancies are seen in a small percentage of patients with primary mediastinal germ cell tumors (PMGct). case report: A 29-year-old male patient with a nonseminomatous primary mediastinal germ cell tumor was diagnosed with Acute Megakaryocytic Leukemia. serum lactate dehydrogenase (LDH) elevation was a diagnostic clue. We discussed our case with a review of literature. conclusion: Oncologists should be aware of the association of PMGct with hematologic malignancies and consider this phenomenon as a differential diagnosis when LDH elevation is present in patients with PMGct.

  • Acute Megakaryocytic Leukemia associated with primary mediastinal germ cell tumor a case report
    Annals of Oncology, 2012
    Co-Authors: Emi Noguchi, Yasushi Omuro, Yoshiharu Maeda, M Kudo, Tatsu Shimoyama, Eisaku Sasaki, Rumiko Okamoto, S Horiguchi, Tunekazu Hishima, Tsuneo Sasaki
    Abstract:

    ABSTRACT A 29-year-old man was referred to our hospital complaining of chest pain and dyspnea on exercise. Computed tomography (CT) scan demonstrated a 9 × 8 cm mass in the left-sided anterior mediastinum. An ultrasonography showed no mass in the bilateral testis. A CT-guided biopsy was carried out twice but a few clusters of malignant tumor cells from uncertain histology could be obtained. On the basis of predominant midline tumor distribution, relatively young patient's age, male sex and increased serum hCG, b-hCG, AFP and LDH, we diagnosed primary mediastinal germ cell tumor (PMGCT), cT1N0M0S2, stage IIIB, with IGCCCG poor risk. He received standard cisplatin, etoposide and bleomycin (BEP) chemotherapy and the tumor markers returned to the normal level after two cycles of BEP. After he received four cycles of BEP, the tumor markers remain within normal range but a CT scan showed increased size of the mass. He underwent surgical resection of the mass. The pathologic examination revealed a remaining non-seminomatous tumor mainly composed of teratoma. He was planned to receive additional two cycles of BEP. Approximately one month after surgery, the serum LDH level rose. The hCG and AFP remained within normal ranges and a CT scan showed no evidence of recurrence of PMGCT. After he received an additional cycle of BEP, the serum LDH continued to rise for a month and finally large atypical cells appeared in the peripheral blood, which were count for 3% of the whole blood cells. Bilateral bone marrow aspiration resulted in dry tap, and bone marrow biopsy confirmed a diagnosis of Acute Megakaryocytic Leukemia (M7) by the French–American–British (FAB) classification. He received induction chemotherapy of idarubicin–cytarabine for the Leukemia.

Emi Noguchi - One of the best experts on this subject based on the ideXlab platform.

  • a case of Acute Megakaryocytic Leukemia associated with a nonseminomatous primary mediastinal germ cell tumor diagnosed through elevation of serum lactate dehydrogenase
    International Journal of Case Reports and Images, 2015
    Co-Authors: Emi Noguchi, Yasushi Omuro, Yoshiharu Maeda, Tsuneo Sasaki
    Abstract:

    Introduction: Hematologic malignancies are seen in a small percentage of patients with primary mediastinal germ cell tumors (PMGct). case report: A 29-year-old male patient with a nonseminomatous primary mediastinal germ cell tumor was diagnosed with Acute Megakaryocytic Leukemia. serum lactate dehydrogenase (LDH) elevation was a diagnostic clue. We discussed our case with a review of literature. conclusion: Oncologists should be aware of the association of PMGct with hematologic malignancies and consider this phenomenon as a differential diagnosis when LDH elevation is present in patients with PMGct.

  • Acute Megakaryocytic Leukemia associated with primary mediastinal germ cell tumor a case report
    Annals of Oncology, 2012
    Co-Authors: Emi Noguchi, Yasushi Omuro, Yoshiharu Maeda, M Kudo, Tatsu Shimoyama, Eisaku Sasaki, Rumiko Okamoto, S Horiguchi, Tunekazu Hishima, Tsuneo Sasaki
    Abstract:

    ABSTRACT A 29-year-old man was referred to our hospital complaining of chest pain and dyspnea on exercise. Computed tomography (CT) scan demonstrated a 9 × 8 cm mass in the left-sided anterior mediastinum. An ultrasonography showed no mass in the bilateral testis. A CT-guided biopsy was carried out twice but a few clusters of malignant tumor cells from uncertain histology could be obtained. On the basis of predominant midline tumor distribution, relatively young patient's age, male sex and increased serum hCG, b-hCG, AFP and LDH, we diagnosed primary mediastinal germ cell tumor (PMGCT), cT1N0M0S2, stage IIIB, with IGCCCG poor risk. He received standard cisplatin, etoposide and bleomycin (BEP) chemotherapy and the tumor markers returned to the normal level after two cycles of BEP. After he received four cycles of BEP, the tumor markers remain within normal range but a CT scan showed increased size of the mass. He underwent surgical resection of the mass. The pathologic examination revealed a remaining non-seminomatous tumor mainly composed of teratoma. He was planned to receive additional two cycles of BEP. Approximately one month after surgery, the serum LDH level rose. The hCG and AFP remained within normal ranges and a CT scan showed no evidence of recurrence of PMGCT. After he received an additional cycle of BEP, the serum LDH continued to rise for a month and finally large atypical cells appeared in the peripheral blood, which were count for 3% of the whole blood cells. Bilateral bone marrow aspiration resulted in dry tap, and bone marrow biopsy confirmed a diagnosis of Acute Megakaryocytic Leukemia (M7) by the French–American–British (FAB) classification. He received induction chemotherapy of idarubicin–cytarabine for the Leukemia.

Larry H. Matherly - One of the best experts on this subject based on the ideXlab platform.

  • Overexpression of GATA1 Confers Resistance to Chemotherapy in Acute Megakaryocytic Leukemia
    PloS one, 2013
    Co-Authors: John Timothy Caldwell, Alan A Dombkowski, Steven Buck, Larry H. Matherly, Holly Edwards, Jeffrey W. Taub
    Abstract:

    It has been previously shown that Acute myeloid Leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with Acute Megakaryocytic Leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the Megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.

  • a unique role of gata1s in down syndrome Acute Megakaryocytic Leukemia biology and therapy
    PLOS ONE, 2011
    Co-Authors: Ana C Xavier, Alan A Dombkowski, Steven Buck, Holly Edwards, Chengzhi Xie, Tugce B Balci, Jason N Berman, Graham Dellaire, Larry H. Matherly
    Abstract:

    Background Acute Megakaryocytic Leukemia (AMkL) in Down syndrome (DS) children is uniformly associated with somatic GATA1 mutations, which result in the synthesis of a shorter protein (GATA1s) with altered transactivation activity compared to the wild-type GATA1. It is not fully established whether leukemogenesis and therapeutic responses in DS AMkL patients are due to loss of the wild-type GATA1 or due to a unique function of GATA1s.

  • overexpression of gata1 confers chemotherapy resistance in pediatric Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Alan A Dombkowski, Mark Stout, Steven Buck, Larry H. Matherly, Chengzhi Xie, Maggie Keller, Jeffrey W. Taub
    Abstract:

    Abstract 2039 Poster Board II-16 Acute Megakaryocytic Leukemia (AMkL; M7) is a biologically heterogeneous form of AML, representing ∼10% of pediatric and 1-2% of adult AML cases. AMkL is the most common AML subtype of children with Down syndrome (DS). DS children with AMkL have an excellent prognosis with EFS rates of 80-100% when treated with ara-C/anthracycline-based protocols, in contrast to the Disclosures: No relevant conflicts of interest to declare.

  • runx1 regulates phosphoinositide 3 kinase akt pathway role in chemotherapy sensitivity in Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Jeffrey W. Taub, Alan A Dombkowski, Katherine M Lafiura, Steven Buck, Chengzhi Xie, Julie L Boerner, Larry H. Matherly
    Abstract:

    RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in Acute Leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in Acute Leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with Acute Megakaryocytic Leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antiLeukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

  • mutational spectrum at gata1 provides insights into mutagenesis and leukemogenesis in down syndrome
    Blood, 2009
    Co-Authors: Diane C Cabelof, Jeffrey W. Taub, Larry H. Matherly, Hiral Patel, Qing Chen, Holly Van Remmen
    Abstract:

    Down syndrome (DS) children have a unique genetic susceptibility to develop Leukemia, in particular, Acute Megakaryocytic Leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of Leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-β-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop Leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-β-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.

Alan A Dombkowski - One of the best experts on this subject based on the ideXlab platform.

  • Overexpression of GATA1 Confers Resistance to Chemotherapy in Acute Megakaryocytic Leukemia
    PloS one, 2013
    Co-Authors: John Timothy Caldwell, Alan A Dombkowski, Steven Buck, Larry H. Matherly, Holly Edwards, Jeffrey W. Taub
    Abstract:

    It has been previously shown that Acute myeloid Leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with Acute Megakaryocytic Leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the Megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.

  • a unique role of gata1s in down syndrome Acute Megakaryocytic Leukemia biology and therapy
    PLOS ONE, 2011
    Co-Authors: Ana C Xavier, Alan A Dombkowski, Steven Buck, Holly Edwards, Chengzhi Xie, Tugce B Balci, Jason N Berman, Graham Dellaire, Larry H. Matherly
    Abstract:

    Background Acute Megakaryocytic Leukemia (AMkL) in Down syndrome (DS) children is uniformly associated with somatic GATA1 mutations, which result in the synthesis of a shorter protein (GATA1s) with altered transactivation activity compared to the wild-type GATA1. It is not fully established whether leukemogenesis and therapeutic responses in DS AMkL patients are due to loss of the wild-type GATA1 or due to a unique function of GATA1s.

  • overexpression of gata1 confers chemotherapy resistance in pediatric Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Alan A Dombkowski, Mark Stout, Steven Buck, Larry H. Matherly, Chengzhi Xie, Maggie Keller, Jeffrey W. Taub
    Abstract:

    Abstract 2039 Poster Board II-16 Acute Megakaryocytic Leukemia (AMkL; M7) is a biologically heterogeneous form of AML, representing ∼10% of pediatric and 1-2% of adult AML cases. AMkL is the most common AML subtype of children with Down syndrome (DS). DS children with AMkL have an excellent prognosis with EFS rates of 80-100% when treated with ara-C/anthracycline-based protocols, in contrast to the Disclosures: No relevant conflicts of interest to declare.

  • runx1 regulates phosphoinositide 3 kinase akt pathway role in chemotherapy sensitivity in Acute Megakaryocytic Leukemia
    Blood, 2009
    Co-Authors: Holly Edwards, Jeffrey W. Taub, Alan A Dombkowski, Katherine M Lafiura, Steven Buck, Chengzhi Xie, Julie L Boerner, Larry H. Matherly
    Abstract:

    RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in Acute Leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in Acute Leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with Acute Megakaryocytic Leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antiLeukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

  • The role of the proto-oncogene ETS2 in Acute Megakaryocytic Leukemia biology and therapy
    Leukemia, 2008
    Co-Authors: Katherine M Lafiura, Alan A Dombkowski, Q Chen, S G Payton, S A Buck, S Salagrama, A E Diakiw, L H Matherly, J W Taub
    Abstract:

    Acute myeloid Leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the Acute Megakaryocytic Leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1. Several chromosome 21-localized transcription factor oncogenes including ETS2 may contribute to the unique features of DS AMkL. ETS2 transcripts measured by real-time RT–PCR were 1.8- and 4.1-fold, respectively, higher in DS and non-DS megakaryoblasts than those in non-DS myeloblasts. In a doxycycline-inducible erythroLeukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to Megakaryocytic phenotypic switch independent of GATA1 levels. Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of Megakaryocytic differentiation. In the K562pTet-on/ETS2 cells, ETS2 induction conferred differences in sensitivities to ara-C and daunorubicin, depending on GATA1 levels. These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.