Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis but facilitates termination of emergency (stress) granulopoiesis

Olatundun Williams, Liping Hu, Weiqi Huang, Priyam Patel, Elizabeth T. Bartom, Ling Bei, Elizabeth Hjort, Christina Hijiya, Elizabeth A. Eklund*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Age-associated bone marrow changes include myeloid skewing and mutations that lead to clonal hematopoiesis. Molecular mechanisms for these events are ill defined, but decreased expression of Irf8/Icsbp (interferon regulatory factor 8/interferon consensus sequence binding protein) in aging hematopoietic stem cells may contribute. Irf8 functions as a leukemia suppressor for chronic myeloid leukemia, and young Irf8−/− mice have neutrophilia with progression to acute myeloid leukemia (AML) with aging. Irf8 is also required to terminate emergency granulopoiesis during the innate immune response, suggesting this may be the physiologic counterpart to leukemia suppression by this transcription factor. Identifying Irf8 effectors may define mediators of both events and thus contributors to age-related bone marrow disorders. In this study, we identified RASSF5 (encoding Nore1) as an Irf8 target gene and investigated the role of Nore1 in hematopoiesis. We found Irf8 activates RASSF5 transcription and increases Nore1a expression during emergency granulopoiesis. Similar to Irf8−/− mice, we found that young Rassf5−/− mice had increased neutrophils and progressed to AML with aging. We identified enhanced DNA damage, excess clonal hematopoiesis, and a distinct mutation profile in hematopoietic stem cells from aging Rassf5−/− mice compared with wildtype. We found sustained emergency granulopoiesis in Rassf5−/− mice, with repeated episodes accelerating AML, also similar to Irf8−/− mice. Identifying Nore1a downstream from Irf8 defines a pathway involved in leukemia suppression and the innate immune response and suggests a novel molecular mechanism contributing to age-related clonal myeloid disorders.

Original languageEnglish (US)
Article number104867
JournalJournal of Biological Chemistry
Volume299
Issue number7
DOIs
StatePublished - Jul 2023

Keywords

  • apoptosis
  • gene regulation
  • hematopoiesis
  • innate immune response
  • myeloid leukemia

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis but facilitates termination of emergency (stress) granulopoiesis'. Together they form a unique fingerprint.

Cite this