Research Papers:

Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation

Malalage N. Peiris, April N. Meyer, Dalida Warda, Alexandre Rosa Campos and Daniel J. Donoghue _

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Oncotarget. 2022; 13:659-676. https://doi.org/10.18632/oncotarget.28228

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Malalage N. Peiris1, April N. Meyer1, Dalida Warda1, Alexandre Rosa Campos2 and Daniel J. Donoghue1,3

1 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92037, USA

2 Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA

3 UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA

Correspondence to:

Daniel J. Donoghue, email: [email protected]

Keywords: oncogenic fusion protein; chromosomal translocation; protein interactome; phosphoproteome; stem cell leukemia/lymphoma

Received: March 06, 2022     Accepted: April 19, 2022     Published: May 11, 2022

Copyright: © 2022 Peiris et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

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