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.