Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Abstract

Significance Myeloproliferative neoplasms (MPN) are chronic hematopoietic disorders characterized by clonal proliferation of mature myeloid elements. A subset of MPNs transforms to acute myeloid leukemia (AML). The mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. We have characterized the somatic mutational spectrum of post-MPN AML and demonstrate that somatic tumor protein 53 ( TP53 ) mutations are common in JAK2 V617F - mutant, post-MPN AML but not in chronic-phase MPN. We demonstrate that expression of JAK2 V617F combined with Tp53 loss in a murine model leads to fully penetrant AML in vivo . We have characterized this model and used it to test therapeutic strategies. These data reveal novel insights into the pathogenesis of, and potential therapeutic strategies for, leukemic transformation.