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

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating an 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 haematopoietic progenitors, which were transplanted into immunodeficient mice. Cells expressing MYB–GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33 and CD117), and of basophilic differentiation (CD203c and FcϵRI). UT‐7 cells also showed basophilic differentiation after MYB–GATA1 transfection. A transcriptomic study identified nine 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 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 basophilic differentiation of MYB–GATA1‐expressing UT‐7 cells, thus demonstrating the importance of this pathway in the basophilic differentiation of leukaemic 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, because of better stability. Our results highlight the role of IL‐33 and NGF receptors in the basophilic differentiation of normal and leukaemic cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.