Oncotarget

Research Papers:

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

Jolanda Sarno, Angela M. Savino, Chiara Buracchi, Chiara Palmi, Stefania Pinto, Cristina Bugarin, Astraea Jager, Silvia Bresolin, Ruth C. Barber, Daniela Silvestri, Shai Israeli, Martin J.S. Dyer, Giovanni Cazzaniga, Garry P. Nolan, Andrea Biondi _, Kara L. Davis and Giuseppe Gaipa

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Oncotarget. 2018; 9:22872-22885. https://doi.org/10.18632/oncotarget.25089

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Abstract

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

Correspondence to:

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

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.


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