Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations

Abstract

Key Points• MYC translocations represent a genetic subgroup of NOTCH1-independent T-ALL clustered within the TAL/LMO category.• MYC translocations are secondary abnormalities, which appear to be associated with induction failure and relapse.MYC translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ∼6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYC translocations were significantly associated with the TAL/LMO subtype of T-ALL (P 5 .018) and trisomies 6 (P < .001) and 7 (P < .001). Within the TAL/LMO subtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYC translocations; specifically, 77 were upregulated and 71 downregulated in those with MYC translocations. The poor prognostic marker, CD44, was among the upregulated genes. MYC translocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse. (Blood. 2014;124(24):3577-3582)

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

“…In fact, a novel non-TCR translocation joining HOXA11-AS to MIR181A1HG on chromosome 1q32 was associated with overexpression of HOXA genes; interestingly, the 1q32 region was recently described to be rearranged with MYC in a case of T-ALL 29 and might represent a novel region of chromosomal rearrangement holding actively transcribed sequences. In addition, RNAseq allowed the identification of complex intrachromosomal 19p13 rearrangements and amplifications producing an out-of-frame MAST3-C19orf10 fusion, probably causing PTEN inactivation, and amplification and overexpression of NOTCH3 and JAK3, both located on 19p13.…”

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

“…10,16,17 All patients or their parents/guardians gave informed consent to sample collection and molecular analyses, in agreement with the Declaration of Helsinki. The study was approved by the local bio-ethical committee (research project 2014-025).…”

“…9 Interestingly, cooperative genetic defects have been described in T-ALL, suggesting that perturbation of specific cell processes are needed for the development of overt leukemia. 10,11 Translocations causing TAL/LMO, TLX1, TLX3, MYB, MEF2C, NKX2-1/2, or HOXA over-expression define distinct gene expression signatures and are known as "type A" abnormalities. 6,[12][13][14] These rearrangements co-occur with multiple mutations and imbalances, named "type B" abnormalities, which activate oncogenic signaling cascades, including JAK/STAT, PI3K/AKT, and RAS/MEK/ERK.…”

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

“…69 In another 6% of adult and childhood T-ALL patients, MYC is ectopically activated due to a MYC translocation; importantly, these patients usually do not have NOTCH1-activating mutations. 71 MYC may also activate NOTCH1 via a positive feedback mechanism, as MYC suppresses the expression of miRNA-30, which targets the 3' untranslated region of NOTCH1 ( Figure 2C). 72 Accordingly, treatment of T-ALL xenografted mice with the bromodomain protein inhibitor JQ1 results in decreased MYC levels and also reverses MYC-induced resistance to GSI.…”