Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis

Abstract

While many aspects of blood production are now well understood, the spatial organization of myeloid differentiation in the bone marrow (BM) remains unknown. Here, we use imaging to track granulocyte/macrophage progenitor (GMP) behavior during emergency and leukemic myelopoiesis. At steady state, we find individual GMPs scattered throughout the BM. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. We describe how the timed release of important BM niche signals (SCF, IL-1β, G-CSF, TGF-β, CXCL4) and activation of an inducible Irf8/β-catenin progenitor self-renewal network controls the transient formation of regenerating GMP clusters. In leukemia, we show that GMP clusters are constantly produced due to persistent activation of the self-renewal network and lack of termination cytokines that normally restore stem cell quiescence. Our results uncover a previously unrecognized dynamic behavior of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukemia.

Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

“…Notably, in damaged and diseased conditions, myeloid‐biased MPPs expand and drive a majority of blood cell production . A similar expansion is seen in downstream committed GMPs after myeloablative stress in a localized fashion . These shifts are accompanied by a decrease in HSC self‐renewal, suggesting that HSCs increase their rate of asymmetric cell division to generate more myeloid‐biased progenitors in stress hematopoiesis.…”

“…Indeed, a subset of lymphoid progenitors appears to localize close to the bone surface; however, while most stages of B cell development are dependent on the perivascular niches . It is not clear what cells create niches for MPPs and GMPs although GMP expansion depends on factors from the vasculature, such as SCF . As certain AMLs are proposed to arise from GMP‐like leukemia initiating cells (LICs), it is of great importance to understand how GMPs are interacting with the bone marrow niche.…”

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

“…Myeloid cells are critical effectors and regulators of tissue regeneration, innate and adaptive immune response [1]. Malfunction or dysregulation of myelopoiesis is tightly associated with various human blood diseases including acute myeloid leukemia (AML) [2]. Previous studies have illustrated the essential role of several transcription factors for normal vertebrate myelopoiesis, including Spi1 , C/ebpα , Gcsfr , Irf8 , and Gfi1 [3–7].…”

GMP-ing to Spatial Conclusions about Emergency and Leukemic Myelopoiesis

“…In a recent issue of Nature, Hérault et al (2017) uncover a unique spatiotemporal mechanism of granulocyte-macrophage progenitors (GMPs) employed in emergency hematopoiesis that is also hijacked in leukemia. …”

“…In a recent issue of Nature , Hérault et al employ imaging approaches that have unveiled a unique spatial organization of GMPs that is important for tuning their capacity to proliferate, differentiate, and respond to negative feedback in the niche. This spatial orientation is also employed during emergency hematopoiesis and hijacked during leukemia (Hérault et al, 2017). …”