Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function.

PURPOSE OF REVIEW: Recent discoveries have provided evidence for mechanistic links between the master regulator of hematopoiesis GATA2 and the key component of interferon and innate immunity signaling pathways, interferon-regulatory factor-8 (IRF8). These links have important implications for the control of myeloid differentiation in physiological and pathological states. RECENT FINDINGS: GATA2 deficiency resulting from loss of the Gata2 -77 enhancer in progenitors triggers an alarm that instigates the transcriptional induction of innate immune signaling and distorts a myeloid differentiation program. This pathological alteration renders progenitors hyperresponsive to interferon γ, toll-like receptor and interleukin-6 signaling and impaired in granulocyte-macrophage colony-stimulating factor signaling. IRF8 upregulation in -77-/- progenitors promotes monocyte and dendritic cell differentiation while suppressing granulocytic differentiation. As PU.1 promotes transcription of Irf8 and other myeloid and B-lineage genes, GATA2-mediated repression of these genes opposes the PU.1-dependent activating mechanism. SUMMARY: As GATA2 deficiency syndrome is an immunodeficiency disorder often involving myelodysplastic syndromes and acute myeloid leukemia, elucidating how GATA2 commissions and decommissions genome activity and developmental regulatory programs will unveil mechanisms that go awry when GATA2 levels and/or activities are disrupted.

Human GATA2 mutations and hematologic disease: how many paths to pathogenesis?

The surge of human genetic information, enabled by increasingly facile and economically feasible genomic technologies, has accelerated discoveries on the relationship of germline genetic variation to hematologic diseases. For example, germline variation in GATA2, encoding a vital transcriptional regulator of multilineage hematopoiesis, creates a predisposition to bone marrow failure and acute myeloid leukemia termed GATA2 deficiency syndrome. More than 300 GATA2 variants representing missense, truncating, and noncoding enhancer mutations have been documented. Although these variants can diminish GATA2 expression and/or function, the functional ramifications of many variants are unknown. Studies using genetic rescue and knockin mouse systems have established that GATA2 mutations differentially affect molecular processes in distinct target genes and within a single target cell. Considering that target genes for a transcription factor can differ in sensitivity to altered levels of the factor, and transcriptional mechanisms are often cell type specific, the context-dependent consequences of GATA2 mutations in experimental systems portend the complex phenotypes and interindividual variation of GATA2 deficiency syndrome. This review documents GATA2 human genetics and the state of efforts to traverse from physiological insights to pathogenic mechanisms.