Summary Subversion of transcription factor (TF) activity in hematopoietic stem/progenitor cells (HSPCs) leads to the development of therapy-resistant leukemic stem cells (LSCs) that drive fulminant acute myeloid leukemia (AML). Using a conditional mouse model where zinc-finger TF Gata2 was deleted specifically in hematopoietic cells, we show that knockout of Gata2 leads to rapid and complete cell-autonomous loss of adult hematopoietic stem cells. By using short hairpin RNAi to target GATA2 , we also identify a requirement for GATA2 in human HSPCs. In Meis1a/Hoxa9 -driven AML, deletion of Gata2 impedes maintenance and self-renewal of LSCs. Ablation of Gata2 enforces an LSC-specific program of enhanced apoptosis, exemplified by attenuation of anti-apoptotic factor BCL2, and re-instigation of myeloid differentiation––which is characteristically blocked in AML. Thus, GATA2 acts as a critical regulator of normal and leukemic stem cells and mediates transcriptional networks that may be exploited therapeutically to target key facets of LSC behavior in AML.

Vukovic et al. report that Hif-1α and Hif-2α are not required for leukemia stem cell maintenance and AML propagation, but they act synergistically to suppress leukemia development in mice. Furthermore, knockout of HIF-2α or pharmacological inhibition of the HIF pathway in human AML cells has no impact on their survival and proliferation under hypoxic conditions.

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Atherosclerosis, an inflammatory disorder of the vasculature and the underlying cause of cardiovascular disease, is responsible for one in three global deaths. Consumption of active food ingredients such as omega-3...

During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other co-morbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes.

GATA2, a zinc finger transcription factor predominantly expressed in hematopoietic cells, acts as an essential regulator of hematopoietic stem cell generation, survival and functionality. Loss and gain of GATA2 expression has been implicated in myelodysplastic syndrome and acute myeloid leukemia (AML) yet the precise biological impact of GATA2 expression on human AML cell fate decisions remains ambiguous. Herein, we performed large-scale bioinformatics that demonstrated relatively frequent GATA2 overexpression in AML patients as well as select human AML (or AML-like) cell lines. By using shRNAi to target GATA2 in these AML cell lines, and an AML cell line expressing normal levels of GATA2, we found that inhibition of GATA2 caused attenuated cell proliferation and enhanced apoptosis exclusively in AML cell lines that overexpress GATA2. We proceeded to pharmacologically inhibit GATA2 in concert with AML chemotherapeutics and found this augmented cell killing in AML cell lines that overexpress GATA2, but not in an AML cell line expressing normal levels of GATA2. These data indicate that inhibition of GATA2 enhances chemotherapy-mediated apoptosis in human AML cells overexpressing GATA2. Thus, we define novel insights into the oncogenic role of GATA2 in human AML cells and suggest the potential utilization of transient GATA2 therapeutic targeting in AML.

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