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.
Antimicrobial resistance (AMR) is a critical issue in health care in terms of mortality, quality of services, and financial damage. In the battle against AMR, it is crucial to recognize the impacts of all four domains, namely, mankind, livestock, agriculture, and the ecosystem. Many sociocultural and financial practices that are widespread in the world have made resistance management extremely complicated. Several pathways, including hospital effluent, agricultural waste, and wastewater treatment facilities, have been identified as potential routes for the spread of resistant bacteria and their resistance genes in soil and surrounding ecosystems. The overuse of uncontrolled antibiotics and improper treatment and recycled wastewater are among the contributors to AMR. Health-care organizations have begun to address AMR, although they are currently in the early stages. In this review, we provide a brief overview of AMR development processes, the worldwide burden and drivers of AMR, current knowledge gaps, monitoring methodologies, and global mitigation measures in the development and spread of AMR in the environment.
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.
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