BCR-ABL1 Mediates Up-regulation of Fyn in Chronic Myelogenous Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2008 Jan 9

PMID 18180382

Citations 26

Authors

Kechen Ban

Yin Gao

Hesham M Amin

Adrienne Howard

Claudia Miller

Quan Lin

Xiaohong Leng

Mark Munsell

Menashe Bar-Eli

Ralph B Arlinghaus

Joya Chandra

Affiliations

Soon will be listed here.

Abstract

Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.

Citing Articles

Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting.

Outhwaite I, Singh S, Berger B, Knapp S, Chodera J, Seeliger M Elife. 2023; 12.

PMID: 38047771 PMC: 10769483. DOI: 10.7554/eLife.86189.

Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson's Disease.

Saminathan H, Ghosh A, Zhang D, Song C, Jin H, Anantharam V Front Pharmacol. 2021; 12:631375.

PMID: 33995031 PMC: 8113680. DOI: 10.3389/fphar.2021.631375.

Recent advances in understanding chronic myeloid leukemia: where do we stand?.

Kumar R, Krause D Fac Rev. 2021; 10:35.

PMID: 33977288 PMC: 8103906. DOI: 10.12703/r/10-35.

Explainable drug sensitivity prediction through cancer pathway enrichment.

Tang Y, Gottlieb A Sci Rep. 2021; 11(1):3128.

PMID: 33542382 PMC: 7862690. DOI: 10.1038/s41598-021-82612-7.

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future.

Minciacchi V, Kumar R, Krause D Cells. 2021; 10(1).

PMID: 33435150 PMC: 7827482. DOI: 10.3390/cells10010117.

References

Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80. DOI: 10.1126/science.1062538. View

Juric D, Lacayo N, Ramsey M, Racevskis J, Wiernik P, Rowe J . Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias. J Clin Oncol. 2007; 25(11):1341-9. DOI: 10.1200/JCO.2006.09.3534. View

Donato N, Wu J, Stapley J, Gallick G, Lin H, Arlinghaus R . BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003; 101(2):690-8. DOI: 10.1182/blood.V101.2.690. View

Chandra J, Hackbarth J, Le S, Loegering D, Bone N, Bruzek L . Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. Blood. 2003; 102(13):4512-9. DOI: 10.1182/blood-2003-02-0562. View

Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D . Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004; 36(5):453-61. DOI: 10.1038/ng1343. View

Palacios E, Weiss A . Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene. 2004; 23(48):7990-8000. DOI: 10.1038/sj.onc.1208074. View

Warmuth M, Druker B, Emmerich B, Hallek M . Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res. 1996; 56(15):3589-96. View

Klucher K, Lopez D, Daley G . Secondary mutation maintains the transformed state in BaF3 cells with inducible BCR/ABL expression. Blood. 1998; 91(10):3927-34. View

Ptasznik A, Nakata Y, Kalota A, Emerson S, Gewirtz A . Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med. 2004; 10(11):1187-9. DOI: 10.1038/nm1127. View

10.

Doggrell S . BMS-354825: a novel drug with potential for the treatment of imatinib-resistant chronic myeloid leukaemia. Expert Opin Investig Drugs. 2005; 14(1):89-91. DOI: 10.1517/13543784.14.1.89. View

11.

Chandra J, Tracy J, Loegering D, Flatten K, Verstovsek S, Beran M . Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance. Blood. 2005; 107(6):2501-6. PMC: 1895739. DOI: 10.1182/blood-2005-07-2966. View

12.

Radich J, Dai H, Mao M, Oehler V, Schelter J, Druker B . Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006; 103(8):2794-9. PMC: 1413797. DOI: 10.1073/pnas.0510423103. View

13.

Meyn 3rd M, Wilson M, Abdi F, Fahey N, Schiavone A, Wu J . Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. J Biol Chem. 2006; 281(41):30907-16. DOI: 10.1074/jbc.M605902200. View

14.

Van Etten R . Oncogenic signaling: new insights and controversies from chronic myeloid leukemia. J Exp Med. 2007; 204(3):461-5. PMC: 2137897. DOI: 10.1084/jem.20062335. View

15.

Mow B, Chandra J, Svingen P, Hallgren C, Weisberg E, Kottke T . Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002; 99(2):664-71. DOI: 10.1182/blood.v99.2.664. View