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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.

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


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.


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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