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, Giuseppe Gaipa

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)22872-22885
Number of pages14
Issue number33
StatePublished - 1 May 2018
Externally publishedYes


  • Acute lymphoblastic leukemia
  • Cell signaling
  • Mass cytometry
  • Minimal residual disease
  • Signal transduction inhibitors


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