MYB deregulation from a EWSR1 - MYB fusion at leukemic evolution of a JAK2 V617F positive primary myelofibrosis

Background Although Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are usually not aggressive, the type and the number of molecular lesions impact greatly on leukemic transformation. Indeed, the molecular background underlying progression is still largely unexplored even though ASXL1 , IDH1/2, SRSF2 , and TP53 mutations, together with adverse karyotypic changes, place the patient at high risk of leukemic transformation. Case presentation Our patient, a 64-year old man with a diagnosis of JAK2 V617F primary myelofibrosis (PMF) had an unusually rapid leukemic transformation. Genomic profiling showed that TET2 and SRSF2 mutations were also present. At leukemic transformation, the patient developed a complex chromosome rearrangement producing a EWSR1 - MYB fusion. Remarkably, the expression of MYB and of its target BCL2 was, respectively, ≥4.7 and ≥2.8 fold higher at leukemic transformation than after chemotherapy, when the patient obtained the hematological remission. At this time point, the EWSR1 - MYB fusion disappeared while JAK2 V617F , TET2, and SRSF2 mutations, as well as PMF morphological features persisted . Conclusions Rapid leukemic transformation of JAK2 V617F PMF was closely linked to a previously undescribed putative EWSR1-MYB transcription factor which was detected only at disease evolution. We hypothesize that the EWSR1-MYB contributed to leukemia transformation through at least two mechanisms: 1) it sustained MYB expression, and consequently deregulated its target BCL2 , a putative onco-suppressor gene ; and 2) ectopic EWSR1-MYB expression probably fulfilled its own oncogenic potential as demonstrated for other MYB -fusions. As our study confirmed that MYB is recurrently involved in chronic as well as leukemic transformation of PMF, it appears to be a valid molecular marker for tailored treatments.