We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.
- Authors
Mohammadhosseini, Mona; Enright, Trevor; Duvall, Adam; Chitsazan, Alex; Lin, Hsin-Yun; Ors, Aysegul; Davis, Brett A.; Nikolova, Olga; Bresciani, Erica; Diemer, Jamie; Craft, Kathleen; Menezes, Ana Catarina; Merguerian, Matthew; Chong, Shawn; Calvo, Katherine R.; Deuitch, Natalie T.; Glushakow-Smith, Shira; Gritsman, Kira; Godley, Lucy A.; Horwitz, Marshall S.
- Abstract
Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (n = 10) combined with functional analysis of samples from patients with RUNX1-FPD (n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1-FPD and prevent myeloid progression. Editor's summary: Patients with familial platelet disorder not only experience thrombocytopenia and platelet dysfunction but are also at higher risk for developing hematological malignancies. In Mohammadhosseini et al., the authors analyzed samples from patients with familial platelet disorder caused by RUNX1 mutations and found altered myeloid cell differentiation and megakaryopoiesis along with increased inflammatory and prosurvival pathways. These pathways were linked to increased CD74 signaling in patients with preleukemic disease. Genetic and pharmacological inhibition of CD74 or downstream targets JAK1/2 and mTOR in patients' cells or RUNX1 mutant mice limited inflammation and pathogenic differentiation. These results suggest that inhibition of CD74 signaling may be a potential therapeutic strategy for these patients. —Allison Williams
- Subjects
HEMATOPOIETIC stem cells; MYELOID cells; MESSENGER RNA; HEMATOLOGIC malignancies; BONE marrow
- Publication
Science Translational Medicine, 2025, Vol 17, Issue 780, p1
- ISSN
1946-6234
- Publication type
Academic Journal
- DOI
10.1126/scitranslmed.adn9832