Date of Award

8-22-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biochemistry Program

First Advisor

Jiwang Zhang

Abstract

Hematopoiesis is dynamically controlled by an epigenetic landscape that regulates gene transcription. Ten-eleven translocation 2 (TET2) is a Fe2+ and α-ketoglutarate (α-KG)-dependent dioxygenase that regulates the transcriptional status of genes associated with hematopoietic stem cell self-renewal and multiple stages of lineage commitment and differentiation. TET2 mutations are commonly detected in almost all types of hematopoietic malignancies, including myeloproliferative disorder, acute myeloid leukemia, and peripheral T-cell lymphomas. In most cases, TET2 is a founder mutation that occurred in hematopoietic stem/progenitor cells (HSPCs). The mutant HSCs undergo clonal expansion and evolution with the accumulation of additional mutations for malignant transformation. Microbial-stimulated inflammatory signals have been reported to play a critical role in the development of TET2 mutant hematopoietic malignancies. RIPK3 is a key mediator of inflammatory cytokine-induced necroptosis signaling. Animal studies suggested that the RIPK3-mediated pathway is activated in TET2 mutant myeloid cells, which attributes to the increased incidence of coronary heart disease and stroke. However, the role of RIPK3 signaling in the pathogenesis of TET2 mutant hematopoietic malignancies is not studied. Here we report that RIPK3 signaling is required for the development of myeloid malignancies but represses peripheral T cell lymphomas (PTCL) in TET2 knockout (Tet2-/-) mice. Different from TET2-/- mice which develop chronic myelomonocytic leukemia (CMML) after 18 months of age, all TET2 and RIPK3 compound knockout (Tet2-/-Ripk3-/-) mice develop PTCL within 10-15 months with features commonly observed in patients with angioimmunoblastic T cell lymphoma (AITL), a PTCL subtype. Mechanistically, in myeloid progenitor cells, RIPK3 mediates tumor necroptosis factor-α (TNFα)-stimulated proliferation/survival signaling that is essential for CMML pathogenesis; however, in CD4+ T cells, RIPK3 inhibits the differentiation and proliferation of T follicular helper (Tfh) cells by restricting ICOS-stimulated PI3K-AKT signaling. Ripk3 is specifically required in modulating surface ICOS levels by regulating receptor-internalization in Tfh cells as well as receptor shedding into follicular dendritic cells (fDC) respectively. On the other hand, intact TNFα-Ripk3 signaling is essential in conferring enhanced hematopoietic fitness to Tet2-/- HSPCs and myeloid-biased progenitors. Collectively, this study sheds light on novel lineage-specific roles of Ripk3 in regulating Tfh cell homeostasis and myelopoiesis in Tet2 deficient mice.

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