Multiomic studies of a murine model of human mixed phenotype acute leukemia
Mixed phenotype acute leukemia (MPAL) is a rare and highly aggressive leukemia with poorly understood pathobiology. We previously developed a spontaneous mouse model of B/myeloid MPAL. We show that the mouse model of B/myeloid MPAL recapitulates human genetic alterations primarily through epigenetic and transcriptional mechanisms. MPAL cells exhibit a previously unrecognized aberrant DNA repair characterized by characterized by an increased KU80/KU70 expression ratio and profoundly error-prone non-homologous end joining (NHEJ). This aberrant repair signature traces the cellular origin of MPAL to a rare subpopulation of early hematopoietic stem/progenitor cells. Human MPAL cells preferentially engage adjacent end joining and display marked sensitivity to combined inhibition of NHEJ and cancer-selective DNA damage induction. Together, these findings define epigenetic dysregulation as a central driver of MPAL genetic instability and uncover therapeutically actionable vulnerabilities.