# Emergency Myelopoiesis Pathways in the Control of Blood Production

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $816,806

## Abstract

PROJECT DESCRIPTION
 Activation of myeloid differentiation pathways always accompanies blood regeneration after stress, the
development of hematological malignancies and physiological aging. However, our understanding of what activate myelopoiesis in such deregulated conditions is still very limited. Our goals in this NHLBI OIA application
are to (1) decipher the cellular and molecular mechanisms controlling emergency myelopoiesis pathways; (2)
understand how the hijacking of these mechanisms contributes to deregulated hematopoietic stem cell (HSC)
function and blood production in stress, disease and aging; and (3) identify novel targets for therapeutic interventions aimed at correcting blood production in these deregulated contexts. We recently showed that the output of the myeloid lineage at steady state reflects the differential production by HSCs of a small number of myeloid-biased multipotent progenitors (MPP), called MPP2 and MPP3, and a large number of lymphoid-biased
MPPs, known as MPP4 or LMPPs, which both give rise to granulocyte/macrophage progenitors (GMP) and
contribute to myelopoiesis (Pietras et al., 2015). During blood regeneration, we found that HSCs are transiently
induced to overproduce MPP2/3 and that MPP4 are reprogrammed towards almost exclusive myeloid output,
in large part due to cytokine stimulation and the triggering of specific regulatory pathways (Reynaud et al.,
2011; Pietras et al., 2015; 2016). An important consequence of the activation of this myeloid regeneration axis
is the formation of defined GMP clusters in the bone marrow (BM) cavity, which drive the local overproduction
of granulocytes (Hérault et al., submitted). This newly identified process of GMP cluster formation is finely
tuned by the timed release of important BM niche signals, and transient activation of an inducible self-renewal
network in a subset of GMPs. Altogether, the remodeling of the MPP compartment and induction of GMP cluster formation represent novel and targetable mechanisms of emergency myelopoiesis, which are transiently
activated during blood regeneration but are continuously triggered in myeloid malignancies. We are now interested in exploring the contribution of these mechanisms to other deregulated contexts such as inflammation
and aging, and in answering an exciting set of new questions that have directly emerged from these studies. In
particular, we would like to understand the molecular and cellular basis for the functional heterogeneity observed in the MPP and GMP compartments, map the mechanisms of HSC lineage commitment and their links
to the pro-inflammatory BM milieu, and decipher the contribution of the biophysical properties of the BM niche
to HSC and myeloid progenitor fate decisions. We also would like to conduct correlative studies with human
cells and leukemic patient samples to establish whether aberrant activation of similar emergency myelopoiesis
pathways contribute to deregulated blood production in humans. Taken t...

## Key facts

- **NIH application ID:** 10133714
- **Project number:** 5R35HL135763-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Emmanuelle Passegue
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $816,806
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133714

## Citation

> US National Institutes of Health, RePORTER application 10133714, Emergency Myelopoiesis Pathways in the Control of Blood Production (5R35HL135763-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133714. Licensed CC0.

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