Proper blood cell formation by rare, self-renewing hematopoietic stem cells (HSCs) in the bone marrow (BM) results from a complex series of fate decisions that are controlled via an array of genetic, epigenetic and metabolic programs. Notably, mutations in genes regulating these programs often lead to HSC dysfunction and/or the development of hematological malignancies. Recently, somatic mutations in pre-RNA splicing factors such as U2AF1 have been observed in hematopoietic cells of patients with myelodysplastic syndrome (MDS), a heterogeneous and difficult-to-treat clonal blood disorder characterized by cytopenias in one or more blood lineages and the potential to evolve into acute myelogenous leukemia (AML). Notably, U2AF1 mutations are considered early events in MDS pathogenesis, suggesting that aberrant pre-RNA splicing in HSCs drives the evolution to disease by deregulating HSC fate. However, the role of U2AF1 in regulating HSC function in normal hematopoiesis, and the contribution of mutant U2AF1 to disease is unclear. Emerging evidence suggests that MDS, AML and other hematological malignancies are associated with prior or concurrent onset of chronic inflammatory diseases including rheumatoid arthritis, lupus, and obesity, and indeed MDS itself is typically characterized by overproduction of inflammatory cytokines and hyperactive innate immune signaling. Moreover, inflammatory signals such as interleukin-1 (IL-1) can directly impact HSC fate, leading to overproduction of myeloid cells at the expense of self-renewal and balanced lineage output. Strikingly, U2AF1 has been shown to play an important role in regulating cellular responses to inflammation by generating anti-inflammatory splice forms of key immune signaling genes such as MyD88. Thus, we hypothesize that U2AF1 plays a critical role in regulating HSC responses to inflammatory signals, with aberrant splicing leading to hyperactive responses to inflammatory signals, resulting in a positive feedback loop that promotes deregulated blood production and altered HSC self-renewal. We propose that aberrant mRNA splicing and inflammation are therefore mechanistically linked and are crucial drivers of hematopoietic dysfunction and, potentially, evolution to MDS and other blood disorders. This proposal seeks to identify how pre-RNA splicing, and U2AF1 in particular, regulates the self-renewal and differentiation of HSCs in the context of inflammation using a combination of in vitro assays and in vivo mouse models of chronic inflammation using WT and U2AF1S34F transgenic mice. These investigations will fill a significant gap in our understanding of how aberrant splicing promote hematopoietic dysfunction and eventual progression to malignancy, by investigating whether aberrant splicing in U2AF1 mutant HSCs exacerbates their response to inflammatory signaling. Collectively, they will provide needed insight into the role of U2AF1 in regulating HSC responses to inflammation and stand to identify a previously unexplored link between aberrant pre-RNA splicing, chronic inflammation, and the pathogenesis of complex blood disorders such as MDS.

Public Health Relevance

Mutations in the RNA splicing factor U2AF1 are sometimes found in a blood forming hematopoietic stem cells (HSCs) from human patients suffering from myelodysplastic syndrome (MDS), a malignant blood disorder often characterized by impaired blood production and chronic inflammation. The biological significance of U2AF1 in HSC function in health and disease is not well understood; from preliminary data we propose that U2AF1 may play a key role in regulating the ability of HSCs to properly differentiate into new blood cells during inflammation, with mutations impairing the ability of HSCs to limit the negative effects of inflammation on their function. Hence, understanding the importance of U2AF1 in HSC function during inflammatory stress will provide important opportunities to identify its contribution to maintaining normal blood production, and potential ways to correct HSC dysfunction and the potential for evolution to MDS in the context of U2AF1 mutation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Chang, Henry
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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