Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

被引：34

作者：

Dasgupta, Yashodhara ^{[1
]}

Koptyra, Mateusz ^{[1
]}

Hoser, Grazyna ^{[2
]}

Kantekure, Kanchan ^{[3
]}

Roy, Darshan ^{[3
]}

Gornicka, Barbara ^{[4
]}

Nieborowska-Skorska, Margaret ^{[1
]}

Bolton-Gillespie, Elisabeth ^{[1
]}

Cerny-Reiterer, Sabine ^{[5
,6
]}

Muschen, Markus ^{[7
]}

Valent, Peter ^{[5
,6
]}

Wasik, Mariusz A. ^{[3
]}

Richardson, Christine ^{[8
,9
]}

Hantschel, Oliver ^{[10
]}

van der Kuip, Heiko ^{[11
,12
]}

Stoklosa, Tomasz ^{[13
]}

Skorski, Tomasz ^{[1
]}

机构：

[1] Temple Univ, Sch Med, Dept Microbiol & Immunol, 3400 N Broad St,MRB 548, Philadelphia, PA 19140 USA

[2] Med Ctr Postgrad Educ, Dept Clin Cytol, Warsaw, Poland

[3] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[4] Med Univ Warsaw, Dept Pathol, Warsaw, Poland

[5] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria

[6] Ludwig Boltzmann Cluster Oncol, Vienna, Austria

[7] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

[8] Univ N Carolina, Dept Biol Sci, Charlotte, NC 28223 USA

[9] Univ N Carolina, Ctr Bioinformat, Charlotte, NC 28223 USA

[10] Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res, Lausanne, Switzerland

[11] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany

[12] Univ Tubingen, Stuttgart, Germany

[13] Med Univ Warsaw, Dept Immunol, Warsaw, Poland

来源：

BLOOD | 2016年 / 127卷 / 17期

基金：

美国国家卫生研究院; 奥地利科学基金会;

关键词：

CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CELL-DEATH RESPONSE; C-ABL; BCR-ABL; TYROSINE KINASE; DNA-DAMAGE; GENOMIC INSTABILITY; APOPTOTIC RESPONSE;

D O I：

10.1182/blood-2015-11-681171

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2131 / 2143

页数：13

共 78 条

[1]

Agami R, 1999, NATURE, V399, P809

[2] Dissecting the role of aberrant DNA methylation in human leukaemia [J].

Amabile, Giovanni ;

Di Ruscio, Annalisa ;

Mueller, Fabian ;

Welner, Robert S. ;

Yang, Henry ;

Ebralidze, Alexander K. ;

Zhang, Hong ;

Levantini, Elena ;

Qi, Lihua ;

Martinelli, Giovanni ;

Brummelkamp, Thijn ;

Le Beau, Michelle M. ;

Figueroa, Maria E. ;

Bock, Christoph ;

Tenen, Daniel G. .

NATURE COMMUNICATIONS, 2015, 6

[3] Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome c and activation of caspase-3 [J].

Amarante-Mendes, GP ;

Kim, CN ;

Liu, L ;

Huang, Y ;

Perkins, CL ;

Green, DR ;

Bhalla, K .

BLOOD, 1998, 91 (05) :1700-1705

[4] ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia [J].

Asimakopoulos, FA ;

Shteper, PJ ;

Krichevsky, S ;

Fibach, E ;

Polliack, A ;

Rachmilewitz, E ;

Ben-Neriah, Y ;

Ben-Yehuda, D .

BLOOD, 1999, 94 (07) :2452-2460

[5] Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells [J].

Bolton-Gillespie, Elisabeth ;

Schemionek, Mirle ;

Klein, Hans-Ulrich ;

Flis, Sylwia ;

Hoser, Grazyna ;

Lange, Thoralf ;

Nieborowska-Skorska, Margaret ;

Maier, Jacqueline ;

Kerstiens, Linda ;

Koptyra, Mateusz ;

Mueller, Martin C. ;

Modi, Hardik ;

Stoklosa, Tomasz ;

Seferynska, Ilona ;

Bhatia, Ravi ;

Holyoake, Tessa L. ;

Koschmieder, Steffen ;

Skorski, Tomasz .

BLOOD, 2013, 121 (20) :4175-4183

[6] Phosphorylation of spleen tyrosine kinase at tyrosine 348 (pSyk348) may be a marker of advanced phase of Chronic Myeloid Leukemia (CML) [J].

Bourgnea, Celine ;

Janel, Alexandre ;

Berger, Juliette ;

Rapatel, Chantal ;

Tournilhac, Olivier ;

Hermet, Eric ;

Guerci, Agnss ;

Lioret, Frederique ;

Briancon, Aurelie ;

Bamdadd, Mahchid ;

Boiret-Dupre, Nathalie ;

Berger, Marc G. .

LEUKEMIA RESEARCH, 2015, 39 (03) :329-334

[7] Location of the BCR/ABL Fusion Genes on Both Chromosomes 9 in Ph Negative Young CML Patients: An Indian Experience [J].

Brahmbhatt, Manisha M. ;

Trivedi, Pina J. ;

Patel, Dharmesh M. ;

Shukla, Shilin N. ;

Patel, Prabhudas S. .

INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION, 2014, 30 (04) :241-246

[8] Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline [J].

Branford, Susan ;

Yeung, David T. ;

Parker, Wendy T. ;

Roberts, Nicola D. ;

Purins, Leanne ;

Braley, Jodi A. ;

Altamura, Haley K. ;

Yeoman, Alexandra L. ;

Georgievski, Jasmina ;

Jamison, Bronte A. ;

Phillis, Stuart ;

Donaldson, Zoe ;

Leong, Mary ;

Fletcher, Linda ;

Seymour, John F. ;

Grigg, Andrew P. ;

Ross, David M. ;

Hughes, Timothy P. .

BLOOD, 2014, 124 (04) :511-518

[9] Abl tyrosine kinases are required for infection by Shigella flexneri [J].

Burton, EA ;

Plattner, R ;

Pendergast, AM .

EMBO JOURNAL, 2003, 22 (20) :5471-5479

[10] p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation [J].

Canitrot, Y ;

Falinski, R ;

Louat, T ;

Laurent, G ;

Cazaux, C ;

Hoffmann, JS ;

Lautier, D ;

Skorski, T .

BLOOD, 2003, 102 (07) :2632-2637

← 1 2 3 4 5 6 7 8 →