Iacobucci Ilaria, Li Yongjin, Roberts Kathryn G, Dobson Stephanie M, Kim Jaeseung C, Payne-Turner Debbie, Harvey Richard C, Valentine Marcus, McCastlain Kelly, Easton John, Yergeau Donald, Janke Laura J, Shao Ying, Chen I-Ming L, Rusch Michael, Zandi Sasan, Kornblau Steven M, Konopleva Marina, Jabbour Elias, Paietta Elisabeth M, Rowe Jacob M, Pui Ching-Hon, Gastier-Foster Julie, Gu Zhaohui, Reshmi Shalini, Loh Mignon L, Racevskis Janis, Tallman Martin S, Wiernik Peter H, Litzow Mark R, Willman Cheryl L, McPherson John D, Downing James R, Zhang Jinghui, Dick John E, Hunger Stephen P, Mullighan Charles G
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cancer Cell. 2016 Feb 8;29(2):186-200. doi: 10.1016/j.ccell.2015.12.013.
Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.
染色体重排是急性淋巴细胞白血病（ALL）的一个标志，并且是ALL起始的重要事件。我们描述了在费城染色体样（Ph样）ALL中促红细胞生成素受体基因EPOR的四种不同重排。所有这些重排导致EPOR胞质尾部在类似于原发性家族性先天性红细胞增多症中发生突变的残基处截断，同时保留了受体激活所必需的近端酪氨酸，而远端调节残基缺失。这导致EPOR表达失调、对促红细胞生成素刺激超敏以及JAK-STAT激活增强。在小鼠B细胞祖细胞中表达截短的EPOR可在体内诱导ALL。具有EPOR重排的人白血病细胞对JAK-STAT抑制敏感，提示这是高危ALL的一种治疗选择。
