1. CRLF2 expression associates with ICN1 stabilization in T‐cell acute lymphoblastic leukemia
- Author
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Ana Luiza Tardem Maciel, Caroline Pires Poubel, Maria S. Pombo-de-Oliveira, Marcela B. Mansur, Mariana Emerenciano, and Elda Pereira Noronha
- Subjects
Intracellular domain ,Cancer Research ,Lymphoblastic Leukemia ,Mrna expression ,T cell ,Biology ,Ikaros Transcription Factor ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Downregulation and upregulation ,Gene expression ,Genetics ,Transcriptional regulation ,medicine ,Humans ,Receptor, Notch1 ,Receptors, Cytokine ,Protein Stability ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Hematopoietic malignancy ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Protein Binding - 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.
- Published
- 2019