MYB-GATA1 fusion promotes basophilic leukaemia: involvement of IL33 and nerve growth factor receptors

Abstract

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating a MYB-GATA1 fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive hematopoietic progenitors which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33, CD117) and of basophilic differentiation (CD203c, FcƐRI). UT-7 cells also showed basophilic differentiation after MYB-GATA1 transfection. A transcriptomic study identified 9 genes deregulated by both MYB-GATA1 and basophilic differentiation. Induction of three of these genes (CCL23, IL1RL1 and NTRK1) was confirmed in MYB-GATA1-expressing CD34-positive cells by RT-qPCR. IL-33 and NGF (Nerve Growth Factor), the ligands of IL1RL1 and NTRK1, respectively, enhanced the basophilic differentiation of MYB-GATA1-expressing UT-7 cells, thus demonstrating the importance of this pathway in basophilic differentiation of leukemic cells and CD34 positive primary cells. Finally gene reporter assays confirmed that MYB and MYB-GATA1 directly activated NTRK1 and IL1RL1 transcription leading to basophilic skewing of the blasts. MYB-GATA1 is more efficient than MYB due to a better stability. Our results highlight the role of IL-33 and NGF receptors in basophilic differentiation of normal and leukemic cells.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2pNTPR6
via IFTTT