Ducassou Stéphane, Prouzet-Mauléon Valérie, Deau Marie-Céline, Brunet de la Grange Philippe, Cardinaud Bruno, Soueidan Hayssam, Quelen Cathy, Brousset Pierre, Pasquet Jean-Max, Moreau-Gaudry François, Arock Michel, Mahon François-Xavier, Lippert Eric
ACTION Laboratory, INSERM Unit 1218, University of Bordeaux, Bordeaux, France.
Unité d'hématologie oncologie pédiatrique, CHU de Bordeaux, Bordeaux, France.
J Pathol. 2017 Jul;242(3):347-357. doi: 10.1002/path.4908. Epub 2017 May 29.
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.
急性嗜碱性粒细胞白血病（ABL）是急性髓细胞白血病的一种罕见亚型。我们之前描述过在患有ABL的男婴中出现一种复发性的t(X;6)(p11;q23)易位，产生了一个MYB - GATA1融合基因。为了更好地理解其作用，将嵌合型MYB - GATA1转录因子在CD34阳性造血祖细胞中表达，然后移植到免疫缺陷小鼠体内。表达MYB - GATA1的细胞显示未成熟标志物（CD34）、粒细胞系标志物（CD33和CD117）以及嗜碱性分化标志物（CD203c和FcϵRI）的表达增加。UT - 7细胞在转染MYB - GATA1后也显示出嗜碱性分化。一项转录组学研究确定了9个受MYB - GATA1和嗜碱性分化共同调控的基因。通过逆转录定量聚合酶链反应在表达MYB - GATA1的CD34阳性细胞中证实了其中3个基因（CCL23、IL1RL1和NTRK1）的诱导表达。白细胞介素（IL）- 33和神经生长因子（NGF）分别是IL - 1受体样1（IL1RL1）和神经营养受体酪氨酸激酶1（NTRK1）的配体，它们增强了表达MYB - GATA1的UT - 7细胞的嗜碱性分化，从而证明了该通路在白血病细胞和CD34阳性原代细胞嗜碱性分化中的重要性。最后，基因报告分析证实MYB和MYB - GATA1直接激活NTRK1和IL1RL1转录，导致原始细胞向嗜碱性方向偏移。由于稳定性更好，MYB - GATA1比MYB更有效。我们的结果突出了IL - 33和NGF受体在正常细胞和白血病细胞嗜碱性分化中的作用。版权所有© 2017英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
