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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13039-016-0277-1) contains supplementary material, which is available to authorized users.

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