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Title: SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia.
Authors: Sarno, Jolanda
Savino, Angela M.
Buracchi, Chiara
Palmi, Chiara
Pinto, Stefania
Bugarin, Cristina
Jager, Astraea
Bresolin, Silvia
Barber, Ruth C.
Silvestri, Daniela
Israeli, Shai
Dyer, Martin J. S.
Cazzaniga, Giovanni
Nolan, Garry P.
Biondi, Andrea
Davis, Kara L.
Gaipa, Giuseppe
First Published: 1-May-2018
Publisher: Impact Journals
Citation: Oncotarget, 2018, 9 (33), pp. 22872-22885
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.
DOI Link: 10.18632/oncotarget.25089
eISSN: 1949-2553
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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