CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia

• Published in: Experimental & molecular medicine Vol. 51; no. 1; pp. 1 - 15
• Main Authors: Jang, Woori, Park, Joonhong, Kwon, Ahlm, Choi, Hayoung, Kim, Jiyeon, Lee, Gun Dong, Han, Eunhee, Jekarl, Dong Wook, Chae, Hyojin, Han, Kyungja, Yoon, Jae-Ho, Lee, Seok, Chung, Nack-Gyun, Cho, Bin, Kim, Myungshin, Kim, Yonggoo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2019; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 38/90; 45/22; 45/77; 631/208/68; 631/67/1990/283/2125; Acute lymphoblastic leukemia; Adolescent; Adult; Aged; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cdc4 protein; Child; Child, Preschool; Clonal deletion; Copy number; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; DNA Copy Number Variations; DNA Methylation; Down-Regulation; Female; GATA-3 protein; Gene Deletion; Gene expression; Genetic analysis; Humans; Leukemia; Lymphatic leukemia; Lymphocytes T; Male; Medical Biochemistry; Middle Aged; Molecular Medicine; Mutation; Notch1 protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Runx1 protein; Stem Cells; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0195-x

We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B , CDKN2A , and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS , were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism. Acute leukemia: Key genetic characteristics uncovered Crucial genetic events contributing to an aggressive form of leukemia have been identified by researchers in South Korea. T-acute lymphoblastic leukemia (T-ALL) is more common in adults than in children and accounts for around 20% of all leukemia cases. Myungshin Kim and Yonggoo Kim and co-workers at the Catholic University of Korea, Seoul conducted detailed genetic analysis of samples from 102 T-ALL patients aged 2–77 years and compared them with healthy controls. They found that 133 mutations on 6 genes were linked with the disease and showed that the reduced expression of one gene, CDKN2B , occurs in most T-ALL patients. CDKN2B expression levels were affected either by deletion or by modification via high levels of methylation. Biallelic deletion or high levels of methylation of CDKN2B was associated with poor prognosis in T-ALL.