Genomic Analysis Drives Tailored Therapy in Poor Risk Childhood Leukemia

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Cancer cell (Impact Factor: 23.52). 08/2012; 22(2):139-40. DOI: 10.1016/j.ccr.2012.07.012
Source: PubMed


Ph-like acute lymphoblastic leukemia (ALL) is a novel subgroup of high-risk childhood ALL. In this issue of Cancer Cell, Roberts et al. describe the identification of genetic alterations that lead to activated kinase and cytokine receptor signaling in Ph-like ALL and demonstrate that this aberrant signaling can be inhibited effectively.

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    ABSTRACT: Chromosomal rearrangements including translocations, deletions, inversions, and insertions are common genetic alterations in cancer. Over 1,000 recurrent chromosome rearrangements have been reported so far in different human tumors ( Most of these chromosome rearrangements are associated with specific tumor types and bear distinctive diagnostic and prognostic significance. Molecular characterization of these rearrangements has revealed numerous cancer genes, including novel fusion genes, and their normal and aberrant interactions involved in tumorigenesis, and has identified myriad therapeutic targets. With the help of advanced high-throughput technologies, many cryptic chromosome rearrangements undetectable by conventional cytogenetics have recently been discovered and delineated. The understanding of the mechanisms responsible for the formation of recurrent chromosome rearrangements and their biological functions has led to novel treatment regimens that target tumor cells specifically, with minimal impact to normal cells. Here, we review common recurrent chromosome rearrangements in both hematopoietic malignancies and solid tumors, and their clinical significance, with a focus on acquired fusion genes and their therapeutic implications (i.e., pharmacogenetics).
    06/2013; 1(2). DOI:10.1007/s40142-013-0011-9
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    ABSTRACT: The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), play a central role in the control of B-cell development, which is dependent on a sequence of cell fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-B cell receptor signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL specific signalling networks will highlight their application in BCP-ALL therapy.Leukemia accepted article preview online, 06 May 2015. doi:10.1038/leu.2015.113.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2015; 29(8). DOI:10.1038/leu.2015.113 · 10.43 Impact Factor


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