H2.0-like Homeobox Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia

SummaryHomeobox domain-containing transcription factors are important regulators of hematopoiesis. Here, we report that increased levels of nonclustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (n = 601, p = 2.3 × 10−6). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells and as a prognostic marker and therapeutic target in AML

Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment

How hematopoietic stem cells coordinate the regulation of opposing cellular mechanisms like self-renewal and differentiation commitment remains unclear. Here, we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of the hematopoietic stem cell (HSC) fate. HSCs lacking Satb1 displayed defective self-renewal, less quiescence and accelerated lineage commitment, resulting in progressive depletion of functional HSCs. Increased commitment was caused by reduced symmetric self-renewal and increased symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed gene sets involved in HSC activation and cellular polarity, including Numb and Myc, two key factors for stem cell fate specification. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment