[R01] Inflammation-Driven Clonal Evolution in RUNX1 Carriers: Mechanisms and Therapeutic Vulnerabilities
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-04-30
Importo max: 610.540 EUR
Paese: US
Descrizione
PROJECT ABSTRACT/SUMMARY
Familial Platelet Disorder (FPD) is an autosomal dominant disorder caused by germline RUNX1 mutations. Over
250 families have been identified, but 18,000 individuals in the USA alone are estimated to exhibit RUNX1-FPD,
but no prevention strategies exist. RUNX1 mutations in FPD establish a preleukemic state in hematopoietic stem
and progenitor cells (HSPCs), predisposing 40-50% of patients to leukemia at a median age of 29. Clonal
hematopoiesis (CH) is more prevalent in RUNX1-FPD with early onset, reaching 67% by age 16 versus <1% in
the healthy population by age 30. CH arises when a single hematopoietic stem cell (HSC) acquires somatic
mutations, enabling the CH clone to outcompete other stem cells in the blood and bone marrow. Increased CH
prevalence poses a high risk of leukemia transformation, demanding early intervention strategies. Our
overarching goal is to uncover the mechanisms driving clonal expansion in RUNX1-FPD, enabling early
identification of patients at risk and prevention of leukemia progression. We discovered that the upregulation of
CD74, a type II transmembrane protein, drives hematopoietic defects by activating prosurvival and inflammatory
pathways in FPD. This proposal aims to identify how the MIF/CD74 axis in FPD confers clonal fitness and to
identify strategies to inhibit this signaling as an early intervention. We identified that the bone marrow
microenvironment in FPD is highly inflammatory, with many upregulated cytokine pathways. Among these, CD74
signaling is aberrantly elevated in FPD HSPCs across CH and leukemic stages, suggesting an unexplored role
of CD74 in clonal fitness and potential as a therapeutic target. Interestingly, CD74 ligand, MIF, is elevated in
progenitors and stromal cells, indicating autocrine and paracrine signaling. Further, CD74 heterodimerizes with
many co-receptors, regulating cytokine milieu and downstream signaling. However, this complex mechanism, its
role in FPD in clonal fitness, and its therapeutic potential remain poorly understood. Our compelling new
preliminary results show that genetic and pharmacological inhibition of MIF/CD74 could improve hematopoietic
defects and suppress myeloid expansion in human samples and murine models with CH. Thus, we hypothesize
that MIF/CD74 signaling drives myeloid bias and confers a fitness advantage to CH-HSPCs during FPD clonal
expansion via autocrine and paracrine mechanisms, driven by increased inflammation. We established a new
mouse model of FPD-CH and 3D cultures, along with access to unique FPD primary samples. We will employ
CRISPR editing, single-cell OMICS, and spatial imaging. We will elucidate 1) MIF/CD74-driven functional
mechanisms that regulate myeloid skewing and clonal fitness of FPD HSPCs by direct and niche-dependent
manners, 2) how CD74 signaling is regulated, and 3) the utility of targeting MIF/CD74 using preclinical models.
Understanding the mechanisms by which FPD-CH HSCs gain a fitness advantage during F
Istituzione: OREGON HEALTH & SCIENCE UNIVERSITY
PI: Anupriya Agarwal
Progetto: 2R01HL155426-05
Settori: National Heart Lung and Blood Institute
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