Identifying Genetic Drivers of Leukemic Transformation in MPNs

Leukemic transformation is a largely fatal event among patients with a myeloproliferative neoplasm (MPN). Previous studies have identified that development of mutations in TP53 is the most frequent somatic mutation leading to leukemic transformation (LT). As such, researchers sought to characterize the functions of TP53 driving leukemic transformation.

Their study, published in Blood, utilized an allelic series of mouse models with JAK2/Trp53 mutant MPNs. According to the authors, only double-mutated inactivation of Trp53 resulted in leukemic transformation to a pure erythroleukemia (PEL), which originated from megakaryocyte-erythroid progenitor cells.

Notably, the bone morphogenetic protein 2/SMAD pathway was aberrantly activated in cases of LT and led to self-renewal of the megakaryocyte-erythroid progenitor population. The researchers noted the mutant PEL was composed of recurrent copy number mutations and damage to DNA. In addition, the authors found that the PEL was “highly sensitive” to combined WEE1 and polymerase inhibition.

The authors suggested that “these observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.”

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