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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous disease. The diagnosis is predominantly based on immunophenotyping. In addition to known cytogenetic abnormalities molecular mutations were recently identified. Here, 90 adult T-ALL cases were investigated for mutations in NOTCH1, FBXW7, PHF6, CDKN2A, DNMT3A, FLT3, PTEN, and RUNX1 using 454 next-generation amplicon sequencing and melting curve analyses. These data were further complemented by FISH, chromosome banding, array CGH, and CDKN2B promoter methylation analyses. NOTCH1 was the most frequently mutated gene with a 71.1% frequency followed by FBXW7 (18.9%), PHF6 (39.5%), DNMT3A (17.8%), RUNX1 (15.5%), PTEN (10.0%), CDKN2A (4.4%), FLT3-ITD (2.2%), and FLT3-TKD (1.1%). In total, 84/90 (93.3%) cases harbored at least one mutation. Combining these data with CDKN2A/B deletions and CDKN2B methylation status, we detected minimum one aberration in 89/90 (98.9%) patients. Survival analyses revealed the subtype as defined by the immunophenotype as the strongest independent prognostic factor. When restricting the survival analysis to the early T-ALL subtype, a strong association of RUNX1 (P = 0.027) and DNMT3A (P = 0.005) mutations with shorter overall survival was observed. In conclusion, RUNX1 and DNMT3A are frequently mutated in T-ALL and are associated with poor prognosis in early T-ALL., (Copyright © 2013 Wiley Periodicals, Inc.)

In acute myeloid leukemia (AML), increased ecotropic virus integration site 1 protein homolog (EVI1) gene expression is prognostically unfavorable. Subsets of cases show 3q26 rearrangements, such as inv(3)(q21q26)/t(3;3)(q21;q26), frequently accompanied by chromosome 7 abnormalities. We investigated whether cytogenetically cryptic EVI1 rearrangements may cause EVI1 overexpression in myeloid malignancies without 3q26 abnormalities and investigated 983 patients with AML (n = 606) or myelodysplastic syndromes (MDS; n = 377) with normal karyotype (CN-AML/CN-MDS, n = 594) or chromosome 7 abnormalities (n = 389) for EVI1 rearrangements using interphase FISH. We identified cytogenetically cryptic EVI1 rearrangements in 27 patients (19 AML, 8 MDS): inv(3)(p24q26) [n = 10]; t(3;21)(q26;q11) [n = 9]; and der(7)t(3;7)(q26;q21) [n = 8]. Elevated EVI1 expression was detected in nearly all cases with cryptic EVI1 rearrangements: Median %EVI1/ABL1 was 92.8 (range: 29.8-146.1) in inv(3)(p24q26), 104.9 (41.4-176.3) in t(3;21)(q26;q11), and 101.8 (4.4-210.4) in der(7)t(3;7)(q26;q21). This was similar to median %EVI1/ABL1 of 73.9 (range: 7.3-585.6) in an independent cohort of inv(3)(q21q26)/t(3;3)(q21;q26) and 67.1 (2.3-410.7) in other 3q26/EVI1 rearrangements. Healthy controls showed median EVI1 expression of 0.5 (range: 0.0-5.8). Using SNP microarray and sequencing analyses, the breakpoints of der(7)t(3;7)(q26;q21) were assigned to CDK6 and centromeric of EVI1, and of t(3;21)(q26;q11) to be within EVI1 and NRIP1. Median overall survival in patients with cryptic EVI1 rearrangements was short, comparable to patients with inv(3)(q21q26)/t(3;3)(q21;q26) or other EVI1 rearrangements. Cryptic EVI1 rearrangements contribute to explain the clinical heterogeneity of CN-AML and are associated with elevated EVI1 expression and an unfavorable prognosis. Screening for cryptic EVI1 rearrangements by FISH may be particularly appropriate in CN-AML with elevated EVI1 expression or in AML/MDS patients with chromosome 7 abnormalities., (Copyright © 2012 Wiley Periodicals, Inc.)

Expression of BAALC, ERG, and MN1 is associated with outcome in normal karyotype acute myeloid leukemia (AML). In this study, the expression of these markers and of EVI1 and CDKN1B was determined using oligonucleotide microarrays in 286 AML comprising all cytogenetic groups. Higher expression of each gene was associated with an inferior outcome: CDKN1B, median overall survival (mOS): 14.9 months vs. not reached (nr), P = 0.005, median event-free survival (mEFS): 9.7 vs. 31.0 months, P = 0.013; BAALC, no impact on OS, mEFS: 6.2 vs. 13.0 months, P = 0.03; ERG: mOS: 12.5 months vs. nr, P = 0.002, mEFS: 8.1 vs. 15.7 months, P = 0.001; MN1: mOS: 12.3 months vs. nr, P = 0.004, mEFS: 8.1 vs. 16.7 months, P = 0.001. A multivariate analysis revealed an independent impact on OS for CDKN1B, ERG, and MN1 expression. A novel score based on BAALC, CDKN1B, ERG, and MN1 expression had an impact on OS and EFS independent of cytogenetics and age. A score taking into account gene expression and karyotype allowed the separation of four prognostic groups with significant differences in OS and EFS (OS at 2 years: 90.4%, 56.4%, 34.0%, 12.6%; mEFS: n.r., 18.1 months, 8.7 months, 2.5 months). The impact on outcome of this score was independent of NPM1mut/FLT3-ITD- status, MLL-PTD, and age., (Copyright © 2011 Wiley-Liss, Inc.)