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Oncotarget. 2018 May 1;9(33):22872-22885. doi: 10.18632/oncotarget.25089. eCollection 2018 May 1.

SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia.

Author information

1
Department of Pediatrics, Bass Center for Childhood Cancer and Blood Disorders, Stanford University, Stanford, CA, USA.
2
M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza, Italy.
3
Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel.
4
Laboratory of Onco-Hematology, Department of Women's and Children's Health, University of Padova, Padova, Italy.
5
Leicester Drug Discovery & Diagnostic Centre, University of Leicester, Leicester, United Kingdom.
6
Biostatistics and Clinic Epidemiology Center, University of Milano Bicocca, Monza, Italy.
7
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
8
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
9
Department of Pediatrics, ASST-Monza, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.

Abstract

Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the CRLF2 gene (hiCRLF2) have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in hiCRLF2 cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples. We uncovered a coordinated signaling network downstream of CRLF2 characterized by co-activation of JAK/STAT, PI3K, and CREB pathways. This CRLF2-driven network could be more effectively disrupted by SRC/ABL inhibition than single-agent JAK or PI3K inhibition, and this could be demonstrated even in primary minimal residual disease (MRD) cells. Our study suggests SCR/ABL inhibition as effective in disrupting the cooperative functional networks present in hiCRLF2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.

KEYWORDS:

acute lymphoblastic leukemia; cell signaling; mass cytometry; minimal residual disease; signal transduction inhibitors

Conflict of interest statement

CONFLICTS OF INTEREST G.P.N. is a paid consultant for Fluidigm, the manufacturer that produced some of the reagents and instrumentation used in this manuscript. All other authors declare nothing to disclose.

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