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

作者：Matteo Brindisi, L. Crisafulli, Matteo Zampini, M. Liturri, Alessia Campagna, L. Lanino, M. Ubezio, G. Todisco, G. Maggioni, Antonio Russo, M. Bacci, Nicla Manes, E. Riva, Denise Ventura, Nicole Pinocchio, Elisa Calvetti, Dario Strina, Tata Nageswara Rao, Matteo Giovanni Della Porta, F. Ficara · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-3985

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 s...