NIH grant: Loss of TET2 Promotes Leukemogenesis by Enhancing NPY-Mediated PRC2 Disruption and CTCFL Chromatin Remodeling (1R21CA307781-01A1)

retained text

NIH grant 1R21CA307781-01A1: Loss of TET2 Promotes Leukemogenesis by Enhancing NPY-Mediated PRC2 Disruption and CTCFL Chromatin Remodeling
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Reuben  Kapur. Award: $407543.
Start: 2026-09-18T00:00:00.
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition driven by somatic
mutations that predispose individuals to hematologic malignancies, including myeloproliferative neoplasms
(MPNs) and acute myeloid leukemia (AML). Although CHIP does not invariably progress to overt disease, its
association with increased mortality and inflammatory disorders highlights the need to define mechanisms
underlying clonal expansion and leukemic transformation. Emerging evidence implicates obesity-induced
diabetes, characterized by chronic hyperglycemia and systemic inflammation, as a major accelerator of CHIP
progression. Neuropeptide Y (NPY), a neuroendocrine mediator dysregulated in diabetes, has recently been
implicated in regulating hematopoietic stem/progenitor cell (HSPC) function within the bone marrow
microenvironment. We hypothesize that obesity-induced NPY signaling creates a permissive niche that promotes
expansion of TET2-mutant hematopoietic clones and accelerates progression to leukemia. Our preliminary
studies demonstrate a strong association between TET2 mutations and dysregulated NPY signaling, including
increased expression of NPY and its receptor, NPY1R, in AML patients harboring TET2 mutations. In obesityinduced
diabetic LepOb/Ob mice carrying Tet2 deficiency, we observed enhanced clonal hematopoiesis and
myeloid expansion, implicating Npy signaling in disease progression. Mechanistically, the NPY promoter
exhibited CpG hypomethylation, consistent with promoter-dependent activation. RNA sequencing of preleukemic
Tet2-deficient LSK (Lin􀃭Kit+Sca1+) cells identified increased expression of the chromatin remodeler
CTCFL, suggesting enhanced transcriptional activation of NPY. Concurrent downregulation of PRC2 complex
components (YY1, EZH1, EED, JARID2, and SUZ12) reduced H3K27me3 deposition and promoted DNA
hypomethylation, further supporting chromatin remodeling and NPY activation. Together, these findings support
a model in which Tet2 loss promotes Npy over expression through coordinated DNA hypomethylation, impaired
PRC2 function, and CTCFL-mediated transcription, driving pre-leukemic stem cell selection, myeloid expansion,
and inflammatory remodeling of the bone marrow microenvironment. Defining this neuroimmune regulatory axis
may identify novel therapeutic strategies to disrupt CHIP progression and prevent leukemic transformation.
LepOb/Ob obesity-induced fatty bone marrow mice, Tet2-deficient mouse models, and competitive bone
marrow transplantation studies are essential for this project because they uniquely recapitulate the
systemic interactions among Tet2-mutant hematopoietic stem/progenitor cells, obesity-associated
inflammation, neuroendocrine Npy signaling, and the bone marrow microenvironment that cannot be
faithfully modeled in vitro. These in vivo models are required to define the mechanisms driving clonal
hematopoiesis progression and leukemic transformation and to evaluate therapeutic strategies with
direct relevance to human CHIP and early myeloid malignancies.

document fetched 2026-09-27 02:45