HighCRLF2expression associates withIKZF1dysfunction in adult acute lymphoblastic leukemia withoutCRLF2rearrangement

Abstract

Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

“…This hypothesis is supported by the strong prognostic significance of certain mutations found already as a major clone at diagnosis. Two such good examples, IKZF1 aberrations and CRLF2 rearrangements that often co-occur in the same leukemias (14,17,18,21,28,62), predict worse prognosis and, as clearly shown in our data, are usually shared between diagnosis and relapse samples.…”

“…Indeed, about two-thirds of kinase-driven ALLs, commonly called "Philadelphia like" (Ph-like) ALLs, demonstrate activation of this pathway similarly to DS-ALL (11,12). The prognosis of these leukemias is worse (11)(12)(13)(14)(15)(16)(17)(18)(19) and a clinical trial incorporating ruxolitinib into the chemotherapy backbone for newly diagnosed patients has been recently opened (NCT02723994).…”

Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros

“…Targeted inhibition of CK2 was able to restore Ikaros binding to the CRLF2 promoter, and repress transcription of the CRLF2 gene in primary B-ALL cells. These data further support the paradigm established in previous studies that: 1) The CK2-Ikaros axis regulates tumor suppression in high-risk B-ALL via transcriptional control of the genes that have a key role in leukemogeneis; and 2) Restoration of Ikaros’ tumor suppressor function occurs following treatment with CK2 inhibitors, which contributes to the therapeutic efficacy of CK2 inhibitors in leukemia (Ge et al, 2016b). …”

Rapid identification of BCR/ABL1‐like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time‐polymerase chain reaction: clinical, prognostic and therapeutic implications

“…The prediction accuracy was indirectly corroborated by the analysis of the genetic features of BCR/ABL1-like ALL cases. As reported in both paediatric and adult cohorts, BCR/ ABL1-like ALL is associated with IKZF1 deletions, CRLF2 deregulation/rearrangements, JAK1/2 mutations, rearrangements of genes coding for TKs and cytokine receptors (Mullighan et al, 2009b,c;Harvey et al, 2010a,b;Yoda et al, 2010;Chen et al, 2012;Asai et al, 2013;Tokunaga et al, 2013;van der Veer et al, 2013;Boer et al, 2015a;Ge et al, 2016;Herold et al, 2017;Jain et al, 2017a;Roberts et al, 2017). Consistently, our BCR/ABL1-like cases frequently carried JAK/STAT pathway mutations, the most recurrent targeting JAK2, followed by CRLF2 and IL7R.…”