BMP2/SMAD pathway activation in JAK2/p53-mutant megakaryocyte/erythroid progenitors promotes leukemic transformation

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.

Automated summary

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) is often fatal, with TP53 mutational inactivation being the most common event. This study demonstrates that biallelic inactivation of Trp53 leads to LT, specifically a pure erythroleukemia (PEL), arising from the megakaryocyte-erythroid progenitor population. Activation of the bone morphogenetic protein 2/SMAD pathway contributes to abnormal self-renewal of megakaryocyte-erythroid progenitors during LT. The Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage, and combination WEE1 and poly(ADP-ribose) polymerase inhibition shows potential as a therapeutic strategy.