asxl1 C-terminal truncation and SRSF2 mutation drive leukemogenesis via immune reprogramming

Additional sex comb-like 1 (ASXL1) and serine/arginine-rich splicing factor 2 (SRSF2) are frequently co-mutated in myeloid malignancies and associated with poor prognosis. To investigate this cooperativity, we developed a novel zebrafish model co-expressing mutant ASXL1 and SRSF2. This model effectively recapitulates key pathological features observed in both murine models and human myeloid neoplasms, including significantly increased monocytosis, dyserythropoiesis, and reduced survival. Transcriptomic profiling of mutant zebrafish marrow cells revealed a dual mechanism: an immune-suppressive marrow microenvironment concurrent with immune activation within the hematopoietic stem and progenitor cell (HSPC) compartment. This dichotomy promotes leukemic stem cell expansion and highlights the intricate interplay between genetic mutations and immune dysregulation, offering insights into potential therapeutic targets.