TY - JOUR
T1 - Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis but facilitates termination of emergency (stress) granulopoiesis
AU - Williams, Olatundun
AU - Hu, Liping
AU - Huang, Weiqi
AU - Patel, Priyam
AU - Bartom, Elizabeth T.
AU - Bei, Ling
AU - Hjort, Elizabeth
AU - Hijiya, Christina
AU - Eklund, Elizabeth A.
N1 - Funding Information:
This work was supported by DK121354 and CX001864 to E. A. E. and a Rally Foundation for Childhood Cancer Research Young Investigator grant 19YIN52 to O. W.
Publisher Copyright:
© 2023
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - apoptosis
KW - gene regulation
KW - hematopoiesis
KW - innate immune response
KW - myeloid leukemia
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U2 - 10.1016/j.jbc.2023.104867
DO - 10.1016/j.jbc.2023.104867
M3 - Article
C2 - 37247756
AN - SCOPUS:85162142957
SN - 0021-9258
VL - 299
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
M1 - 104867
ER -