Dasgupta Yashodhara, Koptyra Mateusz, Hoser Grazyna, Kantekure Kanchan, Roy Darshan, Gornicka Barbara, Nieborowska-Skorska Margaret, Bolton-Gillespie Elisabeth, Cerny-Reiterer Sabine, Müschen Markus, Valent Peter, Wasik Mariusz A, Richardson Christine, Hantschel Oliver, van der Kuip Heiko, Stoklosa Tomasz, Skorski Tomasz
Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
Department of Clinical Cytology, Medical Center for Postgraduate Education, Warsaw, Poland;
Blood. 2016 Apr 28;127(17):2131-43. doi: 10.1182/blood-2015-11-681171. Epub 2016 Feb 10.
Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase.
表达组成型激活的ABL1酪氨酸激酶突变体（BCR-ABL1、TEL-ABL1、NUP214-ABL1）的白血病通常至少含有1个正常的ABL1等位基因。由于致癌性ABL1激酶和正常ABL1激酶可能对细胞行为产生相反的影响，我们研究了正常ABL1在致癌性ABL1激酶诱导的白血病中的作用。与BCR-ABL1-Abl1(+/+)细胞产生的恶性程度较低的慢性粒细胞白血病（CML）慢性期样疾病相比，BCR-ABL1-Abl1(-/-)细胞在小鼠中产生了高度侵袭性的CML急变期样疾病。此外，ABL1的缺失刺激了BCR-ABL1小鼠白血病干细胞的增殖和扩增，阻止了髓系分化，抑制了基因毒性应激诱导的凋亡，并促进了染色体畸变的积累。相反，ABL1激酶活性的变构刺激增强了ABL1酪氨酸激酶抑制剂（伊马替尼和波纳替尼）对表达BCR-ABL1、TEL-ABL1和NUP214-ABL1的人类和小鼠白血病的抗白血病作用。因此，我们推测正常ABL1激酶在表达致癌形式激酶的白血病中表现为肿瘤抑制因子和治疗靶点。
