Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system

Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches

Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system but the molecular mechanisms and their relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the preleukemic disorder Shwachman-Diamond syndrome induces mitochondrial dysfunction, oxidative stress and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the mouse model and a range of human preleukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome, the principal leukemia predisposition syndrome. Collectively, our findings reveal a concept of mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as an actionable determinant of disease outcome in human preleukemia

Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1 -FPD

RUNX1 familial platelet disorder (RUNX1-FPD) is a hematopoietic disorder caused by germline loss-of-function mutations in the RUNX1 gene and characterized by thrombocytopathy, thrombocytopenia, and an increased risk of developing hematologic malignancies, mostly of myeloid origin. Disease pathophysiology has remained incompletely understood, in part because of a shortage of in vivo models recapitulating the germline RUNX1 loss of function found in humans, precluding the study of potential contributions of non-hematopoietic cells to disease pathogenesis. Here, we studied mice harboring a germline hypomorphic mutation of one Runx1 allele with a loss-of-function mutation in the other Runx1 allele (Runx1L148A/-mice), which display many hematologic characteristics found in human RUNX1-FPD patients. Runx1L148A/-mice displayed robust and pronounced thrombocytopenia and myeloid-biased hematopoiesis, associated with an HSC intrinsic reconstitution defect in lymphopoiesis and expansion of myeloid progenitor cell pools. We demonstrate that specific deletion of Runx1 from bone marrow stromal cells in Prrx1-cre;Runx1fl/flmice did not recapitulate these abnormalities, indicating that the hematopoietic abnormalities are intrinsic to the hematopoietic lineage, and arguing against a driving role of the bone marrow microenvironment. In conclusion, we report a RUNX1-FPD mouse model faithfully recapitulating key characteristics of human disease. Findings do not support a driving role of ancillary, non-hematopoietic cells in the disruption of hematopoiesis under homeostatic conditions

Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2bdeficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b