MYB–GATA1 fusion promotes basophilic leukaemia: involvement of interleukin‐33 and nerve growth factor receptors

Acute basophilicleukaemia (ABL) is a rare subtype of acute myeloblasticleukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating an MYB– GATA1 fusion genein male infants with ABL. To better understand its role, the chimeric MYB– GATA1transcription factor was expressed in CD34-positive haematopoietic progenitors, which were transplanted into immunodeficient mice. Cells expressing MYB– GATA1showed increased expression of markers of immaturity ( CD34), of granulocytic lineage ( CD33and CD117), and of basophilicdifferentiation (CD203c and FcϵRI). UT-7 cells also showed basophilicdifferentiation after MYB– GATA1transfection. A transcriptomic study identified nine genes deregulated by both MYB– GATA1and basophilicdifferentiation. Induction of three of these genes ( CCL23, IL1RL1, and NTRK1) was confirmed in MYB– GATA1-expressing CD34-positive cells by reverse transcription quantitative polymerase chain reaction. Interleukin (IL)-33 and nerve growth factor (NGF), the ligands of IL-1 receptor-like 1 ( IL1RL1) and neurotrophic receptor tyrosine kinase 1 (NTRK1), respectively, enhanced the basophilicdifferentiation of MYB– GATA1-expressing UT-7 cells, thus demonstrating the importance of this pathway in the basophilicdifferentiation of leukaemic cells and CD34-positive primary cells. Finally, gene reporter assays confirmed that MYBand MYB– GATA1directly activated NTRK1 and IL1RL1transcription, leading to basophilicskewing of the blasts. MYB– GATA1is more efficient than MYB, because of better stability. Our results highlight the role of IL-33 and NGF receptors in the basophilicdifferentiation of normal and leukaemic cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.