Abstract 3985: MED12L: A novel player in platelet dysfunction in myeloid neoplasms

Abstract Myeloproliferative neoplasms (MPN) impose substantial clinical burden through thrombotic complications and leukemic progression, representing the main determinants of patient morbidity and mortality. These clonal malignancies arise from somatic mutations in hematopoietic stem cells (HSC), most commonly JAK2-V617F. Despite therapeutic advances, molecular mechanisms underlying aberrant megakaryopoiesis and pathologic thrombocytosis remain unmet. This study investigates Mediator complex subunit 12-like (MED12L), a functionally uncharacterized protein, in normal and malignant hematopoiesis, identifying a novel regulatory function in platelet (PLT) turnover dynamics. In JAK2V617F mice genetic ablation of the transcription factor Pbx1 resulted in amelioration of thrombocythemia and erythrocytosis. Transcriptomics analysis of their stem/progenitor cells uncovered downregulation of Med12l. Conversely, in JAK2V617F mice, Med12l was upregulated in common Megakaryocyte (Mk)-Erythroid progenitors and in committed Mk (but not erythroid) precursors, rising the hypothesis that MED12L dysregulation contributes to aberrant PLT homeostasis in myeloid malignancies. To assess the functional significance of MED12L in the hematopoietic system, we studied Med12l knockout (KO) mice and performed systematic hematopoietic characterization under steady-state and stress conditions. We also generated Med12l KO/Jak2V617F compound mutants (JM mice) to assess the impact of MED12L absence in vivo in an MPN setting. Clinical validation utilized MPN and myelodysplastic syndrome cohorts. Our investigations reveal a previously unrecognized role for MED12L in regulating PLT lifespan and turnover. Blood analysis of Med12l-KO mice demonstrated an altered PLT compartment, with increased mean PLT volume, distribution width, area, internal complexity, and elevated surface integrin expression with respect to WT. These findings indicate impaired PLT maturation, supported by a higher frequency of reticulated PLT and increased mitochondrial and endoplasmic reticulum content. In vivo PLT depletion with anti-GPIbα antibody revealed impaired recovery kinetics in KO mice, with delayed bone marrow Mk-primed HSC and Mk-committed progenitor expansion. Critically, in vivo biotinylation studies definitively established accelerated platelet clearance in MED12L absence. Importantly, in JM mice the absence of MED12L counteracted thrombocytosis, a hallmark of MPN, without affecting erythrocytosis. Consistently, scRNA-seq from MPN patients showed a higher proportion of MED12L-expressing platelets compared to healthy donors; similarly, in patients affected by myelodysplastic syndrome we observed a strong correlation between the expression of MED12L in CD34+ cells and platelet features.This study uncovers MED12L as a novel player in platelet biology, highlighting its potential as a therapeutic target in myeloid neoplasms. Citation Format: Matteo Brindisi, Laura Crisafulli, Matteo Zampini, Mirko G. Liturri, Alessia Campagna, Luca B. Lanino, Marta Ubezio, Gabriele Todisco, Giulia Maggioni, Antonio Russo, Monica Bacci, Nicla Manes, Elena Riva, Denise Ventura, Nicole Pinocchio, Elisa Calvetti, Dario Strina, Tata Nageswara Rao, Matteo Della Porta, Francesca Ficara. MED12L: A novel player in platelet dysfunction in myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3985.