# Regulation of emergency hematopoiesis by the ubiquitin-proteasome system

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $615,348

## Abstract

Project Summary
The response to systemic infection and tissue injury requires the rapid adaptation of hematopoietic stem cells
(HSCs) in the bone marrow, which proliferate and divert their differentiation towards the myeloid lineage.
Significant interest has emerged in understanding the signals that trigger this emergency hematopoietic
program. However, the mechanisms that terminate this response of the HSCs and restore tissue
homeostasis remain unknown. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin
ligase glues for the treatment of hematologic diseases has made the Ubiquitin pathway a bona fide target for
cancer therapeutics. Thus, defining how novel E3 ligases function in the bone marrow and investigating their
specific roles in normal and emergency hematopoiesis can lead to novel therapeutic interventions. We have
demonstrated that the E3 ubiquitin ligase Spop restrains the inflammatory activation of HSCs. In the absence
of Spop, systemic inflammation proceeds in an unresolved manner and the sustained response in the HSCs
results in a lethal phenotype reminiscent of hyper-inflammatory syndrome. Our proteomic/biochemical
studies demonstrated that Spop restricts inflammation by targeting the signal transducer Myd88 for
proteasome-dependent degradation. Myd88 accumulation in conjunction with an inflammatory stimulus leads
to Myddosome formation, the hyper-phosphorylation of the Irak4 kinase and activation of a number of
transcription factor pathways (NF-kB, Jun, Pu.1, Cebpb). This proposal defines: (a) the transcriptional and
chromatin landscape changes imposed during initiation and termination of emergency hematopoiesis in the
bone marrow HSC and progenitor cells, (b) the role of the myddosome assembly, signaling and termination
in emergency hematopoiesis and gene regulation and (c) the structural details of myddosome assembly and
termination. The findings of this grant proposal will uncover HSC-intrinsic mechanisms essential for
reestablishing homeostasis following emergency hematopoiesis.

## Key facts

- **NIH application ID:** 10872115
- **Project number:** 5R01HL159175-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Iannis Aifantis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,348
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872115

## Citation

> US National Institutes of Health, RePORTER application 10872115, Regulation of emergency hematopoiesis by the ubiquitin-proteasome system (5R01HL159175-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872115. Licensed CC0.

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