Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in <i>RUNX1</i>-familial platelet disorder.

Abstract

Familial platelet disorder (FPD) is associated with germline <i>RUNX1</i> 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 (<i>n</i> = 10) combined with functional analysis of samples from patients with <i>RUNX1</i>-FPD (<i>n</i> > 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 <i>RUNX1</i>-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. <i>RUNX1</i>-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with <i>RUNX1</i>-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 <i>RUNX1</i>-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 <i>RUNX1</i>-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in <i>RUNX1</i>-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 <i>RUNX1</i>-FPD and prevent myeloid progression.