CRLF2 expression associates with ICN1 stabilization in T‐cell acute lymphoblastic leukemia

Abstract

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high‐risk T‐ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T‐ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T‐ALL. We evaluated two independent series of pediatric T‐ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T‐ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T‐ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1‐PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.

CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

“…We previously demonstrated that NOTCH1/FBXW7 mutations leading to stabilization of the NOTCH1 nuclear protein are associated with CRLF2 overexpression in T‐ALL 7 . In the present study, we found 15% of PTEN mutations in the CRLF2 ‐high subgroup (Figure 1A).…”

“…We previously demonstrated that NOTCH1/FBXW7 mutations leading to stabilization of the NOTCH1 nuclear protein are associated with CRLF2 overexpression in T-ALL. 7 In the present study, we found 15% of PTEN mutations in the CRLF2-high subgroup (Figure 1A). Noteworthy, NOTCH1 regulates PTEN expression and PTEN loss is associated with resistance to pharmacological inhibition of NOTCH1 in T-ALL.…”

“…However, the mechanisms underlying this gene dysregulation remain unknown 4–6 . Our group has been exploring CRLF2 dysregulation in T‐ALL 7 and, due to its correlation with unfavorable prognostic features, we set out to investigate the gene expression profile (GEP) underlying CRLF2 overexpression in this leukemia subtype.…”

Ikaros Proteins in Tumor: Current Perspectives and New Developments

“…In addition, KDM5B expression is downregulated by Ikaros through recruiting HDAC1 to the KDM5B gene promoter, which causes an inhibitory chromatin condition and transcriptional inhibition consequently ( Dhanyamraju et al, 2020 ). Ikaros upregulates the PHF2 expression through chromatin remodeling, as demonstrated by the appearance of increased H3K4me3 in the promoter of the PHF2 gene ( Ge et al, 2016a ; Ge et al, 2018a ; Maciel et al, 2019 ). The expression of ARID5B is positively adjusted by Ikaros, and the loss of a single copy of IKZF1 is associated with low ARID5B expression ( Ge et al, 2018b ).…”