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

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 Neumann, M., "Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations" 121 : 4749-4752, 2013

2 Lee, J. W., "Treatment of children with acute lymphoblastic leukemia with risk group based intensification and omission of cranial irradiation : A Korean study of 295 patients" 63 : 1966-1973, 2016

3 Pui, C. H., "Treatment of acute lymphoblastic leukemia" 354 : 166-178, 2006

4 Trinquand, A., "Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia : a Group for Research in Adult Acute Lymphoblastic Leukemia study" 31 : 4333-4342, 2013

5 Arber, D. A., "The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia" 127 : 2391-2405, 2016

6 Mirebeau, D., "The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951" 91 : 881-885, 2006

7 Grossmann, V., "The molecular profile of adult T-cell acute lymphoblastic leukemia : mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL" 52 : 410-422, 2013

8 Van Vlierberghe, P., "The molecular basis of T cell acute lymphoblastic leukemia" 122 : 3398-3406, 2012

9 Belver, L., "The genetics and mechanisms of T cell acute lymphoblastic leukaemia" 16 : 494-507, 2016

10 Zhang, J., "The genetic basis of early T-cell precursor acute lymphoblastic leukaemia" 481 : 157-163, 2012

11 Kunz, J. B., "Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation" 100 : 1442-1450, 2015

12 Karrman, K., "Pediatric T-cell acute lymphoblastic leukemia" 56 : 89-116, 2017

13 Patrick, K., "Outcome for children and young people with early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003" 166 : 421-424, 2014

14 Mullighan, C. G., "Mutations of NOTCH1, FBXW7, and prognosis in T-lineage acute lymphoblastic leukemia" 94 : 1338-1340, 2009

15 Neumann, M., "Mutational spectrum of adult T-ALL" 6 : 2754-2766, 2015

16 Yu, L., "Microarray detection of multiple recurring submicroscopic chromosomal aberrations in pediatric T-cell acute lymphoblastic leukemia" 25 : 1042-1046, 2011

17 Chim, C. S., "Methylation of p15 and p16genes in adult acute leukemia : lack of prognostic significance" 91 : 2222-2229, 2001

18 Kuchinskaya, E., "Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia(ALL) : results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol" 152 : 615-622, 2011

19 Chopra, A., "Immunophenotypic analysis of T-acute lymphoblastic leukemia. A CD5-based ETP-ALL perspective of non-ETP T-ALL" 92 : 211-218, 2014

20 Richter-Pechanska, P., "Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia" 7 : e523-, 2017

21 Mai, H., "Hypermethylation of p15 gene associated with an inferior poor long-term outcome in childhood acute lymphoblastic leukemia" 142 : 497-504, 2016

22 Kim, M., "Homozygous deletion of CDKN2A(p16, p14)and CDKN2B(p15)genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia : a comparative deletion and hypermethylation study" 195 : 59-65, 2009

23 Perez-Garcia, A., "Genetic loss of SH2B3 in acute lymphoblastic leukemia" 122 : 2425-2432, 2013

24 Schwab, C. J., "Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia : association with cytogenetics and clinical features" 98 : 1081-1088, 2013

25 Gao, J., "GATA family transcriptional factors : emerging suspects in hematologic disorders" 4 : 28-, 2015

26 Batova, A., "Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia" 57 : 832-836, 1997

27 Krieger, D., "Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci : a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia" 95 : 158-162, 2010

28 Danis, E., "Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia" 14 : 1953-1965, 2016

29 Coustan-Smith, E., "Early T-cell precursor leukaemia : a subtype of very high-risk acute lymphoblastic leukaemia" 10 : 147-156, 2009

30 Schafer, V., "EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia" 142 : 1641-1650, 2016

31 Lee, S., "Donor-specific differences in long-term outcomes of myeloablative transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia" 24 : 2110-2119, 2010

32 Herman, J. G., "Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies" 57 : 837-841, 1997

33 Nobori, T., "Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers" 368 : 753-756, 1994

34 Karrman, K., "Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A" 8 : 42-, 2015

35 Scourzic, L., "DNMT3A(R882H)mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice" 30 : 1388-1398, 2016

36 Zhang, X., "DNMT3A and TET2 compete and cooperate to repress lineagespecific transcription factors in hematopoietic stem cells" 48 : 1014-1023, 2016

37 Park, J., "Chromosome abnormalities in T-cell acute lymphoblastic leukemia in Korea" 99 : 279-287, 2014

38 Bertin, R., "CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono-and bi-allelic 9p21 deletions in childhood acute lymphoblastic leukemia" 37 : 44-57, 2003

39 Xie, M., "Age-related mutations associated with clonal hematopoietic expansion and malignancies" 20 : 1472-1478, 2014

40 Wong, I. H., "Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes : potential prognostic implications" 95 : 1942-1949, 2000

41 Hungate, E. A., "A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology" 7 : 10635-, 2016

42 Sulong, S., "A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups" 113 : 100-107, 2009