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Leukemia. 2017 Jul;31(7):1513-1524. doi: 10.1038/leu.2017.61. Epub 2017 Feb 17.

Differential signaling through p190 and p210 BCR-ABL fusion proteins revealed by interactome and phosphoproteome analysis.

Cutler JA1,2,3, Tahir R4,5, Sreenivasamurthy SK4,6, Mitchell C5,7, Renuse S4,8, Nirujogi RS4,6, Patil AH4,6,9, Heydarian M2,3, Wong X10, Wu X2,4, Huang TC1,4,11, Kim MS2,4,12, Reddy KL2,3,13, Pandey A2,4,8,14.

Author information

1
Pre-Doctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Institute of Bioinformatics, International Technology Park, Bangalore, India.
7
Ginkgo Bioworks, Boston, MA, USA.
8
Center for Proteomics Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
School of Biotechnology, KIIT University, Bhubaneswar, India.
10
Laboratory of Developmental and Regenerative Biology, Institute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Immunos, Singapore.
11
Division of Hematology, Department of Internal Medicine, National Taiwan University and National Taiwan University Cancer Center, Taipei, Taiwan.
12
Department of Applied Chemistry, Kyung Hee University, Yongin, South Korea.
13
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
14
Departments of Pathology and Oncology, Johns Hopkins, University School of Medicine, Baltimore, MD, USA.

Abstract

Two major types of leukemogenic BCR-ABL fusion proteins are p190BCR-ABLand p210BCR-ABL. Although the two fusion proteins are closely related, they can lead to different clinical outcomes. A thorough understanding of the signaling programs employed by these two fusion proteins is necessary to explain these clinical differences. We took an integrated approach by coupling protein-protein interaction analysis using biotinylation identification with global phosphorylation analysis to investigate the differences in signaling between these two fusion proteins. Our findings suggest that p190BCR-ABL and p210BCR-ABL differentially activate important signaling pathways, such as JAK-STAT, and engage with molecules that indicate interaction with different subcellular compartments. In the case of p210BCR-ABL, we observed an increased engagement of molecules active proximal to the membrane and in the case of p190BCR-ABL, an engagement of molecules of the cytoskeleton. These differences in signaling could underlie the distinct leukemogenic process induced by these two protein variants.

PMID:
28210003
DOI:
10.1038/leu.2017.61
[Indexed for MEDLINE]

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