CRLF2 expression associates with ICN1 stabilisation in T‐cell acute lymphoblastic leukaemia

Abstract

T‐cell acute lymphoblastic leukaemia (T‐ALL) is an aggressive haematopoietic 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 antagonises 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 paediatric 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 = 0.04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilisation are associated with CRLF2 overexpression.

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