Clinical and cytogenetic features of a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias: Rare T‐cell receptor gene rearrangements are associated with poor outcome

Abstract

Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.

Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma

“…25 Interestingly, the NRF3 locus maps to this region, 11 and further experiments will be required to determine whether the Nrf3 gene is affected in the translocations causing different lymphoblastic lymphomas. [26][27][28] In conclusion, our studies demonstrate that the absence of Nrf3 renders mice more susceptible to lymphomagenesis, particularly of T-cell origin, in response to chemical carcinogenesis. Our results suggest that the Nrf3 deficiency can predispose to development of hematologic malignancies.…”

Promoter DNA Methylation Pattern Identifies Prognostic Subgroups in Childhood T-Cell Acute Lymphoblastic Leukemia

“…Over the past 30 years a remarkable improvement in ALL treatment has occurred, but the therapy success rate for T-ALL is lower than for precursor B-cell lymphoblastic leukemia. T-ALL harbors a multitude of genetic alterations, frequently associated with rearrangements of T cell antigen receptor genes with involved fusion genes, such as TLX1 , LMO1, LMO2, TAL1 and LYL1 [1], [2]. Mutations of NOTCH1, FBXW7 , PTEN and WT1 have also been reported in several studies [1], [3].…”

Temporal Changes in PTEN and mTORC2 Regulation of Hematopoietic Stem Cell Self-Renewal and Leukemia Suppression

“…Pten loss-of-function mutations occur frequently in T-precursor ALL (T-ALL) and Pten is inactivated in some acute myeloid leukemias (AML) by mutations, promoter methylation, or transcriptional repression (Dahia et al, 1999; Gutierrez et al, 2009; Larson Gedman et al, 2009; Yoshimi et al, 2011). While B-ALL usually presents in young children and rarely involves Pten deletion (Mullighan et al, 2011) pediatric T-ALL exhibits an older mean age of presentation (~9-10 years of age) (Smith et al, 1999; Clappier et al, 2007; Karrman et al, 2009) and commonly involves Pten deletion or other mutations that activate PI3-kinase pathway signaling (Gutierrez et al, 2009). …”