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

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posted on 2018-06-11, 09:14 authored by 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, Giuseppe Gaipa
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.

Funding

The authors would like to acknowledge MRCT Centre of Therapeutic Discovery for antibody generation/development supporting the progression of this project and Associazione Italiana Emato-Oncologia Pediatrica (AIEOP) centers for their continuous support. This work was supported by Comitato M.L. Verga; Fondazione Tettamanti; Fondazione Benedetta è la Vita ONLUS (J.S.); Fondazione Italiana per la Ricerca sul Cancro (FIRC-AIRC 19488 to J.S.); Grant Ric. Corrente OBG 2006/02/R/001822; Associazione Italiana per la Ricerca sul Cancro (AIRC; to A.B., G.C.); Fondazione Cariplo (A.B.); Ministero dell’Istruzione, Università e Ricerca (MIUR; to A.B.); Israel Science Foundation grant 1178/12and ERA-NET TRANSCALL (S.I.); NetApp St. Baldrick’s Foundation Scholar award and CureSearch Young Investigator award (K.L.D.); Wellcome Trust Grant 097828/Z/11/Z and the Medical Research Council Grant MC-PC_13037 (M.J.S.D).

History

Citation

Oncotarget, 2018, 9 (33), pp. 22872-22885

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

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  • VoR (Version of Record)

Published in

Oncotarget

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Impact Journals

eissn

1949-2553

Acceptance date

2018-03-19

Copyright date

2018

Available date

2018-06-11

Publisher version

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=25089&path[]=78635

Language

en

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