RESUMO
Outgrowth of a mutated hematopoietic stem/progenitor clone and its descendants, also known as clonal hematopoiesis, has long been considered as either a potential forerunner to hematologic malignancy or as a clinically silent phase in leukemia that antedates symptomatic disease. That definition of clonal hematopoiesis has now been expanded to encompass patients who harbor specific genetic/epigenetic mutations that lead to clonal hematopoiesis of indeterminate potential (CHIP) and, with it, a relatively heightened risk for both myeloid malignancy and atherosclerosis during aging. In this review, we provide contemporary insights into the cellular and molecular basis for CHIP and explore the relationship of CHIP to myeloid malignancy and atherosclerosis. We also discuss emerging strategies to explore CHIP biology and clinical targeting of CHIP related malignancy and cardiovascular disease.
Assuntos
Aterosclerose , Leucemia , Neoplasias , Aterosclerose/genética , Aterosclerose/patologia , Hematopoiese Clonal/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Mutação , Neoplasias/genéticaRESUMO
Hematopoietic stem cells naturally traffic out of their bone marrow niches into the peripheral blood. This natural trafficking process can be enhanced with numerous pharmacologic agents - a process termed "mobilization" - and the mobilized stem cells can be collected for transplantation. We review the current state of mobilization with an update on recent clinical trials and new biologic mechanisms regulating stem cell trafficking. We propose that hematopoietic mobilization can be used to answer questions regarding hematopoietic stem cell heterogeneity, can be used for non-toxic conditioning of patients receiving stem cell transplants, and can enhance gene editing and gene therapy strategies to cure genetic diseases.
Assuntos
Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Transplante de Células-TroncoRESUMO
During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other comorbidities, 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.
Assuntos
Deficiência de GATA2 , Idoso , Envelhecimento/genética , Animais , Proliferação de Células , Fator de Transcrição GATA2/genética , Hematopoese , Células-Tronco Hematopoéticas , Humanos , CamundongosRESUMO
Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of "stemness," such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system as a well-established paradigm of stem cell biology to evaluate Zeb1-mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knock out (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid-onset thymic atrophy and apoptosis-driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multilineage differentiation block were observed in Zeb1-KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multilineage differentiation genes and of cell polarity consisting of cytoskeleton-, lipid metabolism/lipid membrane-, and cell adhesion-related genes. Notably, epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1-KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients, and Zeb1 KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9- and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically coordinating HSC self-renewal, apoptotic, and multilineage differentiation fates required to suppress leukemic potential in AML.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Deleção de Genes , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/patologia , Proteínas Supressoras de Tumor/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Bone marrow resident hematopoietic stem cells (HSCs) are responsible for the lifetime generation of the wide profusion of blood and immune cell types found in the body. In addition, therapeutically, in the context of bone marrow transplantation, HSCs have been successfully deployed to restore normal blood-forming capacity in patients being treated with high-dose chemotherapy for hematologic malignancies. The known ability of bone marrow transplantation to either restore or reset the immune system and to engender immune tolerance has suggested that HSCs may be applied therapeutically for a wider range of clinical conditions, including immunological/autoimmune disorders and allogeneic organ transplantation. Herein, we describe a flow-cytometry-based method to isolate mouse HSCs for continued experimental investigation into such therapeutic uses.
Assuntos
Separação Celular/métodos , Citometria de Fluxo/métodos , Células-Tronco Hematopoéticas/citologia , Animais , Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Humanos , CamundongosRESUMO
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.
Assuntos
Apoptose , Proliferação de Células , Fator de Transcrição GATA2/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Antineoplásicos/uso terapêutico , Fator de Transcrição GATA2/genética , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Células THP-1RESUMO
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.