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

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// Jolanda Sarno 1, 2 , Angela M. Savino 3 , Chiara Buracchi 2 , Chiara Palmi 2 , Stefania Pinto 2 , Cristina Bugarin 2 , Astraea Jager 1 , Silvia Bresolin 4 , Ruth C. Barber 5 , Daniela Silvestri 6 , Shai Israeli 3 , Martin J.S. Dyer 7 , Giovanni Cazzaniga 2 , Garry P. Nolan 8 , Andrea Biondi 2, 9 , Kara L. Davis 1, * and Giuseppe Gaipa 2, * 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 * These authors have contributed equally to this work Correspondence to: Andrea Biondi, email: abiondi.unimib@gmail.com 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 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 hiCRLF 2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.