GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.

Stemness-associated cell states are linked to chemotherapy resistance in AML. We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance.

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation.

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.

Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks.

Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide.

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.