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.
Sarno, J., Savino, A., Buracchi, C., Palmi, C., Pinto, S., Bugarin, C., et al. (2018). SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia. ONCOTARGET, 9(33), 22872-22885 [10.18632/oncotarget.25089].
Citazione: | Sarno, J., Savino, A., Buracchi, C., Palmi, C., Pinto, S., Bugarin, C., et al. (2018). SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia. ONCOTARGET, 9(33), 22872-22885 [10.18632/oncotarget.25089]. | |
Tipo: | Articolo in rivista - Articolo scientifico | |
Carattere della pubblicazione: | Scientifica | |
Presenza di un coautore afferente ad Istituzioni straniere: | Si | |
Titolo: | SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia | |
Autori: | Sarno, J; Savino, A; Buracchi, C; Palmi, C; Pinto, S; Bugarin, C; Jager, A; Bresolin, S; Barber, R; Silvestri, D; Israeli, S; Dyer, M; Cazzaniga, G; Nolan, G; Biondi, A; Davis, K; Gaipa, G | |
Autori: | SARNO, JOLANDA (Primo) Gaipa, Giuseppe (Ultimo) | |
Data di pubblicazione: | 2018 | |
Lingua: | English | |
Rivista: | ONCOTARGET | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.18632/oncotarget.25089 | |
Appare nelle tipologie: | 01 - Articolo su rivista |
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