3016 – SECRETORY MPP3 REINFORCE MYELOID DIFFERENTIATION TRAJECTORY AND AMPLIFY MYELOID CELL PRODUCTION

Abstract

Hematopoietic stem cells (HSC) and their downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. However, we are still lacking the resolution of myeloid differentiation trajectories and cellular heterogeneity in MPP populations. Here, we show that myeloid-biased MPP3 are composed of several molecular subsets, with a distinct population of myeloid-primed cells with high endoplasmic reticulum (ER) volume and FcgR expression. Interestingly, FcgR+/ERhi MPP3 secrete high levels of IL-6 and TNFa cytokines upon inflammatory stimuli, and have faster division rates than ERlo MPP3. Moreover, condition media containing cytokines secreted by stimulated MPP3 promotes myeloid cell production from naïve HSCs, MPP3, and MPP4. These results suggest that FcgR+/ERhi MPP3 represent a transitional population toward granulocyte/macrophage progenitor (GMP) commitment, which could function as a self-reinforcing amplification compartment for myeloid differentiation in stress conditions. We next use our inducible Scl-tTA:TRE-BCR/ABL (BA) mouse model of myeloproliferative neoplasm (MPN) to investigate their role in leukemia. We find a massive expansion of FcgR+/ERhi MPP3 associated with a molecular remodeling of the MPP3 compartment and constitutive secretion of a unique set of cytokines, distinct from the ones produced in stress conditions. In particular, Galectin-3 (Gal3) is highly expressed by leukemic MPP3, and BA mice deficient for Gal3 (BA:Gal3-/-) show significantly reduced numbers of FcgR+/ERhi MPP3 and GMPs, and delayed disease onset. These results demonstrate the importance of FcgR+/ERhi MPP3 in amplifying myeloid cell production. Together, they identify a novel regulatory function for a subset of secretory MPP3 that controls myeloid differentiation through lineage-priming and cytokine production.