SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia
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Jolanda Sarno1,2, Angela M. Savino3, Chiara Buracchi2, Chiara Palmi2, Stefania Pinto2, Cristina Bugarin2, Astraea Jager1, Silvia Bresolin4, Ruth C. Barber5, Daniela Silvestri6, Shai Israeli3, Martin J.S. Dyer7, Giovanni Cazzaniga2, Garry P. Nolan8, Andrea Biondi2,9, Kara L. Davis1,* and Giuseppe Gaipa2,*
1Department of Pediatrics, Bass Center for Childhood Cancer and Blood Disorders, Stanford University, Stanford, CA, USA
2M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza, Italy
3Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel
4Laboratory of Onco-Hematology, Department of Women’s and Children’s Health, University of Padova, Padova, Italy
5Leicester Drug Discovery & Diagnostic Centre, University of Leicester, Leicester, United Kingdom
6Biostatistics and Clinic Epidemiology Center, University of Milano Bicocca, Monza, Italy
7Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom
8Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
9Department of Pediatrics, ASST-Monza, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy
*These authors have contributed equally to this work
Andrea Biondi, email: [email protected]
Keywords: acute lymphoblastic leukemia; cell signaling; signal transduction inhibitors; mass cytometry; minimal residual disease
Received: October 13, 2017 Accepted: March 19, 2018 Published: May 1, 2018
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.
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