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.


METHODS
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.
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Tiziana
T
Pierini
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Danika
D
Di Giacomo
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Valentina
V
Pierini
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Paolo
P
Gorello
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Gianluca
G
Barba
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Anair Graciela
AG
Lema Fernandez
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Fabrizia
F
Pellanera
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Tamara
T
Iannotti
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Franca
F
Falzetti
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Roberta
R
La Starza
Hematology and Bone Marrow Transplantation Unit, University of Perugia, C.R.E.O., Piazzale Menghini n.9, 06132 Perugia, Italy.
Cristina
C
Mecucci
Leukemic transformation; MYB; PMF