T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL.

https://biblio.ugent.be/publication/3126347/file/3130738.pdf

The molecular basis of T cell acute lymphoblastic leukemia

The chromosomal translocation t(7;9) in human T-cell acute lymphoblastic leukaemia (T-ALL) results in deregulated expression of a truncated, activated form of Notch 1 (TAN1) under the control of the T-cell receptor-beta (TCRB) locus. Although TAN1 efficiently induces T-ALL in mouse models, t(7;9) is present in less than 1% of human T-ALL cases. The recent discovery of novel activating mutations in NOTCH1 in more than 50% of human T-ALL samples has made it clear that Notch 1 is far more important in human T-ALL pathogenesis than previously suspected.

Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic.

The genetics and mechanisms of T cell acute lymphoblastic leukaemia

Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

The homeobox (HOX) genes are a highly conserved family of homeodomain-containing transcription factors that specify cell identity in early development and, subsequently, in a number of adult processes including hematopoiesis. The dysregulation of HOX genes is associated with a number of malignancies including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), where they have been shown to support the immortalization of leukemic cells both as chimeric partners in fusion genes and when overexpressed in their wild-type form. This review covers our current understanding of the role of HOX genes in normal hematopoiesis, AML and ALL, with particular emphasis on the similarities and differences of HOX function in these contexts, their hematopoietic downstream gene targets and implications for therapy.

The role of HOX genes in normal hematopoiesis and acute leukemia.

Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRalphadelta gene (14q11), the TCRbeta gene (7q34) and to a lesser extent the TCRgamma gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv(7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T- and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.

https://biblio.ugent.be/publication/349753/file/6793619.pdf

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias

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A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias