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, Keel Sioban, Castilla Lucio H, Demir Emek, Mohammed Hisham, Liu Paul, Agarwal Anupriya
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Division of Oncological Sciences, Oregon Health & Science University, Portland, OR 97239, USA.
Sci Transl Med. 2025 Jan 8;17(780):eadn9832. doi: 10.1126/scitranslmed.adn9832.
Familial platelet disorder (FPD) is associated with germline 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 ( = 10) combined with functional analysis of samples from patients with -FPD ( > 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 -FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. -FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with -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 -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 -FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in -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 -FPD and prevent myeloid progression.
家族性血小板疾病（FPD）与种系突变相关，可导致白血病前期状态并增加患白血病的风险。目前，尚无预防白血病进展的干预策略。单细胞RNA测序（n = 10）结合对-FPD患者（n>75）样本的功能分析表明，由于促生存和炎症途径的激活增加，FPD造血干细胞和祖细胞（HSPCs）表现出髓系分化增加和巨核细胞生成受抑制。-FPD患者的骨髓中细胞因子环境升高，对HSPCs施加慢性炎症应激。-FPD HSPCs偏向髓系，自我更新增加，且对炎症介导的耗竭具有抗性。与健康对照相比，-FPD患者白血病前期骨髓中CD74的转录本和蛋白表达较高，患者转化为白血病后仍保持高水平。此外，与健康对照相比，-FPD HSPCs中CD74介导的信号传导被夸大，导致mTOR和JAK/STAT途径激活，细胞因子产生增加。用ISO-1及其下游靶点JAK1/2和mTOR对CD74进行基因和药理学靶向，可在体外和体内逆转-FPD的分化缺陷并减轻炎症。我们的结果强调，炎症是-FPD发病机制中的早期事件，CD74信号传导是这种炎症的驱动因素之一。重新利用JAK1/2抑制剂（鲁索替尼）和mTOR抑制剂（西罗莫司），并在临床环境中促进CD74抑制剂作为早期干预策略的进展，将有利于改善-FPD患者的表型并预防髓系进展。
