Pediatric T‐cell acute lymphoblastic leukemia

Abstract

The most common pediatric malignancy is acute lymphoblastic leukemia (ALL), of which T‐cell ALL (T‐ALL) comprises 10–15% of cases. T‐ALL arises in the thymus from an immature thymocyte as a consequence of a stepwise accumulation of genetic and epigenetic aberrations. Crucial biological processes, such as differentiation, self‐renewal capacity, proliferation, and apoptosis, are targeted and deranged by several types of neoplasia‐associated genetic alteration, for example, translocations, deletions, and mutations of genes that code for proteins involved in signaling transduction, epigenetic regulation, and transcription. Epigenetically, T‐ALL is characterized by gene expression changes caused by hypermethylation of tumor suppressor genes, histone modifications, and miRNA and lncRNA abnormalities. Although some genetic and gene expression patterns have been associated with certain clinical features, such as immunophenotypic subtype and outcome, none has of yet generally been implemented in clinical routine for treatment decisions. The recent advent of massive parallel sequencing technologies has dramatically increased our knowledge of the genetic blueprint of T‐ALL, revealing numerous fusion genes as well as novel gene mutations. The challenges now are to integrate all genetic and epigenetic data into a coherent understanding of the pathogenesis of T‐ALL and to translate the wealth of information gained in the last few years into clinical use in the form of improved risk stratification and targeted therapies. Here, we provide an overview of pediatric T‐ALL with an emphasis on the acquired genetic alterations that result in this disease. © 2016 Wiley Periodicals, Inc.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…On the other hand, fusion genes are also common (20-30% in T-ALL), generating overexpression of mRNAs with ORFs for wild-type protein (such as TAL1 in STIL-TAL1) (9, 10) or transcripts containing fusions between two truncated ORFs such as SET-NUP214 (11). A number of gene abnormalities in pathways regulating differentiation, proliferation, self-renewal, and survival of T-cell precursors are also found in high frequencies, such as mutations of NOTCH1, JAK-STAT, PI3K-AKT, or RAS-MAPK pathway genes and CDKN2A/2B deletions (2,5,(12)(13)(14)(15).…”

Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype

“…Of the 15% of pediatric cases diagnosed with T-ALL, approximately 15% of these patients are diagnosed early T-precursor ALL (EPT-ALL; refs. [25][26][27][28]. EPT-ALL cells have retained myeloid and stem cell characteristics making it a distinct entity from T-ALL (27,(29)(30)(31).…”

FoxN1-dependent thymic epithelial cells promote T-cell leukemia development

“…T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy thought to arise from the transformation of thymocytes, as supported by similarities in the immunophenotypic, genotypic and transcriptomic profile of T-ALL cases and specific stages of intrathymic T-cell differentiation (1)(2)(3). During intrathymic thymocyte differentiation, transformation events can lead to aberrant expression of oncogenic transcription factors that induce maturation arrest (4). Genetic abnormalities in T-ALL, which include chromosomal translocations, point mutations, and deletions (4), typically result in the activation of signaling pathways commonly involved in cancer, most notably the PTEN/PI3K/AKT, Ras/MAPK and JAK/STAT pathways (5).…”

“…During intrathymic thymocyte differentiation, transformation events can lead to aberrant expression of oncogenic transcription factors that induce maturation arrest (4). Genetic abnormalities in T-ALL, which include chromosomal translocations, point mutations, and deletions (4), typically result in the activation of signaling pathways commonly involved in cancer, most notably the PTEN/PI3K/AKT, Ras/MAPK and JAK/STAT pathways (5). Furthermore, one of the most common genetic alterations and considered a hallmark of T-ALL are NOTCH1-activating point mutations, present in more than 60% of cases (4,5).…”

“…Genetic abnormalities in T-ALL, which include chromosomal translocations, point mutations, and deletions (4), typically result in the activation of signaling pathways commonly involved in cancer, most notably the PTEN/PI3K/AKT, Ras/MAPK and JAK/STAT pathways (5). Furthermore, one of the most common genetic alterations and considered a hallmark of T-ALL are NOTCH1-activating point mutations, present in more than 60% of cases (4,5). The same signaling pathways that are activated by intrinsic oncogenic mutations can also be activated by extrinsic signals provided by stromal cells in organs…”