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.
Highlights
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease resulting from the accumulation of genetic alterations in B-lymphoid precursor cells and represents the most common malignant disease in childhood [1, 2]
This higher basal pSTAT5 level is expected considering that our hiCRLF2 cohort contained two patients bearing mutations in JAK2 (Pt #2: R683G JAK2 mutation and Pt #1 a novel JAK2 insertion, L681-I682 insGL, in exon 16; see Table 1)
Exposing the primary BCP-ALL leukemic cells to these treatments (Supplementary Table 2) and comparing phosphoprotein www.oncotarget.com www.oncotarget.com levels to the TSLP-stimulated condition, we found that the JAKi, ruxolitinib, decreased the TSLP-induced STAT5 activation in hiCRLF2 samples but the response was heterogeneous (p=0.3338) as patients #1, #2 and patient #6 demonstrated a strong pSTAT5 inhibition with ruxolitinib
Summary
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease resulting from the accumulation of genetic alterations in B-lymphoid precursor cells and represents the most common malignant disease in childhood [1, 2]. Subsets of CRLF2-overexpressing cells have been shown to harbor activating mutations in JAK, IL7R and NRAS [11], as well as deletions of the IKZF1 gene [12, 13], which confer poor clinical prognosis [14]. Since these patients respond poorly to standard chemotherapy regimens, there is need to improve our understanding of the biology of this BCP-ALL subtype to devise new therapeutic approaches
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