Green Alexa S, Maciel Thiago T, Hospital Marie-Anne, Yin Chae, Mazed Fetta, Townsend Elizabeth C, Pilorge Sylvain, Lambert Mireille, Paubelle Etienne, Jacquel Arnaud, Zylbersztejn Florence, Decroocq Justine, Poulain Laury, Sujobert Pierre, Jacque Nathalie, Adam Kevin, So Jason C C, Kosmider Olivier, Auberger Patrick, Hermine Olivier, Weinstock David M, Lacombe Catherine, Mayeux Patrick, Vanasse Gary J, Leung Anskar Y, Moura Ivan C, Bouscary Didier, Tamburini Jerome
Institut Cochin, Département Développement, Reproduction, Cancer, CNRS, UMR 8104, INSERM U1016, Paris 75014, France. ; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France. ; Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris 75013, France. ; Department of Hematology, Charles Nicolle University Hospital, Rouen 76000, France.
INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, Paris 75015, France. ; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris 75015, France. ; CNRS ERL 8254, Paris 75015, France. ; Laboratory of Excellence GR-Ex, Paris 75015 , France.
Sci Adv. 2015 Sep 18;1(8):e1500221. doi: 10.1126/sciadv.1500221. eCollection 2015 Sep.
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.
Fms样酪氨酸激酶3内部串联重复（FLT3-ITD）在急性髓系白血病（AML）患者中经常被检测到，并且与不良的长期预后相关。FLT3酪氨酸激酶抑制剂可提供短期疾病控制，但数月内必然会复发。Pim蛋白激酶是AML细胞中表达的致癌性FLT3-ITD靶点。我们发现，在用FLT3抑制剂治疗的AML患者的复发样本中，Pim激酶表达增加。异位表达Pim-2可在FLT3-ITD诱导的骨髓增殖性肿瘤和小鼠AML模型中诱导对FLT3抑制的抗性。令人惊讶的是，我们发现Pim激酶调控FLT3-ITD信号传导，并且它们的药理学或基因抑制可恢复细胞对FLT3抑制剂的敏感性。最后，双重抑制FLT3和Pim激酶可根除包括原发性AML细胞在内的FLT-ITD（+）细胞。同时抑制Pim和FLT3代表了一种有前景的AML治疗新途径。
