Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia

Ge, Yubin; Dombkowski, Alan A.; LaFiura, Katherine M.; Tatman, Dana; Yedidi, Ravikiran S.; Stout, Mark; Buck, Steven; Massey, Gita; Becton, David L.; Weinstein, Howard J.; Ravindranath, Yaddanapudi; Matherly, Larry H.; Taub, Jeffrey W.

doi:10.1182/blood-2005-06-2219

Cited by 95 publications

(96 citation statements)

References 31 publications

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“…These results highlight distinct biological differences between DS and non-DS AMkL cases. Consistent with this notion, in our previous studies using in vitro MTT assays, DS megakaryoblasts were significantly more sensitive to ara-C and daunorubicin than non-DS megakaryoblasts, 10 similar to results reported by others. 11,12 Somatic mutations in exon 2 of the X-linked gene, GATA1, which encodes a zinc-finger transcription factor that is essential for normal erythroid and megakaryocytic differentiation, have been detected exclusively and almost uniformly in all DS AMkL cases, but not in non-DS AML or non-AMkL DS leukemia cases.…”

Section: Introductionsupporting

confidence: 91%

“…Of course, validation of this hypothesis will require further experiments in appropriate DS AMkL cell line models to identify the complex mechanisms responsible for the significantly enhanced chemotherapy sensitivities in DS AMkL compared to non-DS AMkL. 10 In summary, our results with KE and KE-G cell line models suggest that ETS2 likely contributes to the AMkL phenotype in both DS and non-DS children. Furthermore, an apparent cooperation between ETS2 and GATA1 was implied that results in significantly altered sensitivities to chemotherapy drugs used for AMkL, such as ara-C and daunorubicin.…”

Section: Discussionmentioning

confidence: 70%

“…The significantly enhanced in vitro sensitivity to chemotherapy drugs (ara-C and daunorubicin) in DS megakaryoblasts compared to non-DS megarkyoblasts 10 suggests that trisomy 21 and GATA1 mutations may somehow cooperate to modulate chemotherapy drug activity toward DS megakaryoblasts. However, this has not been previously tested.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] This indicates that chromosome 21-localized genes somehow contribute to these unique patterns of drug activity. The uniform detection of GATA1 exon 2 mutations in DS AMkL implies that GATA1 mutations and loss of GATA1 function for GATA1s may also be involved in the enhanced drug sensitivities in DS AMkL.…”

Section: Ets2 Modulates Hematopoietic Lineage Genes and Transcriptionmentioning

confidence: 98%

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The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

LaFiura

Dombkowski

et al. 2007

Leukemia

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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.

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Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Ets2 Modulates Hematopoietic Lineage Genes and Transcriptionmentioning

confidence: 98%

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The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

LaFiura

Dombkowski

et al. 2007

Leukemia

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“…Whole cell lysates were subjected to SDS-polyacrylamide gel electrophoresis, electrophoretically transferred onto polyvinylidene difluoride (PVDF) membranes (Thermo Fisher Inc., Rockford, IL, USA) and immunoblotted with anti-p-CDK2 (Y15) (ab76146) (Abcam, Hong Kong, China), p-CDK1 (Y15) (5757-1), -CDK1 (1484-1), -Wee1 (S2798), -p-CDC25C (S216) (1190-1) -CDK2 (1134-1) (Epitomics, Burlingame, CA, USA), -H4 (07-108), -ac-H4 (06-598) (Millipore, Billerica, MA, USA), -CHK1 (10362-1-AP), (Proteintech, Chicago, IL, USA), -cleaved caspase-3 (9661), -gH2AX (2577), -Wee1 (4936), -GAPDH (2118) (Cell Signaling Technology, Danvers, MA, USA), -CHK1 (sc-8408, Santa Cruz Biotechnology, Santa Cruz, CA, USA) or -b-actin antibody (SigmaAldrich), as previously described. 65,66 Immunoreactive proteins were visualized using the Odyssey Infrared Imaging System (Li-Cor, Lincoln, NE, USA), as described by the manufacturer. Western blots were repeated at least 3 times and one representative blot is shown.…”

Section: In Vitro Cytotoxicity Assaysmentioning

confidence: 99%

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Zhang

Edwards

et al. 2015

Cancer Biology & Therapy

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MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775-and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

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Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

Regalo

Leutz

2013

EMBO Mol Med

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Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phenotypic features of another differentiated tissue, termed metaplasia. In haemato/lymphopoietic malignancies, cell lineage ambiguity is increasingly recorded. Both, metaplasia and biphenotypic leukaemia/lymphoma represent examples of dysregulated cell differentiation that reflect a history of trans-differentiation and/or epigenetic reprogramming. Here we compare the similarity between molecular events of experimental cell trans-differentiation as an emerging therapeutic concept, with lineage confusion, as in metaplasia and dysplasia forecasting tumour development.

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Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia

Cited by 95 publications

References 31 publications

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

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