RESUMEN
Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/uso terapéutico , Autorrenovación de las Células/genética , Daunorrubicina/farmacología , Daunorrubicina/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucotrieno B4/metabolismo , Leucotrieno B4/uso terapéutico , Células Madre Neoplásicas/patologíaRESUMEN
Hemoglobin production during mammalian development is characterized by temporal switches of the genes coding for the α- and ß-globin chains. Defects in this controlled process can lead to hemoglobinapathies such as sickle cell disease and ß-thalassemia. The ability of human embryonic stem cells (hESC) to proceed through hematopoiesis could provide a clinically useful source of red blood cells. However, hESC-derived red cells exhibit an embryonic/fetal, but not adult, mode of hemoglobin expression. The resource described here is a hESC line engineered to express a reporter from its adult globin promoter, providing a screening platform for small molecules that lead to efficient induction of adult globin.
Asunto(s)
Edición Génica , Nucleasas de los Efectores Tipo Activadores de la Transcripción , Adulto , Animales , Línea Celular , Células Madre Embrionarias , Hematopoyesis , Humanos , Nucleasas de los Efectores Tipo Activadores de la Transcripción/genéticaRESUMEN
Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36(+) LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.
Asunto(s)
Adaptación Fisiológica , Tejido Adiposo/patología , Antineoplásicos/farmacología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Antineoplásicos/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/patología , Antígenos CD36/metabolismo , Citoprotección/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Gónadas/patología , Humanos , Inflamación/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Lipólisis/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Neoplásicas/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
Recent studies have significantly improved our understanding of the role microRNAs (miRNAs) play in regulating normal hematopoiesis. miRNAs are critical for maintaining hematopoietic stem cell function and the development of mature progeny. Thus, perhaps it is not surprising that miRNAs serve as oncogenes and tumor suppressors in hematologic malignancies arising from hematopoietic stem and progenitor cells, such as the myeloid disorders. A number of studies have extensively documented the widespread dysregulation of miRNA expression in human acute myeloid leukemia (AML), inspiring numerous explorations of the functional role of miRNAs in myeloid leukemogenesis. While these investigations have confirmed that a large number of miRNAs exhibit altered expression in AML, only a small fraction has been confirmed as functional mediators of AML development or maintenance. Herein, we summarize the miRNAs for which strong experimental evidence supports their functional roles in AML pathogenesis. We also discuss the implications of these studies on the development of miRNA-directed therapies in AML.
