Genomic Analysis Drives Tailored Therapy in Poor Risk Childhood Leukemia

ArticleinCancer cell 22(2):139-40 · August 2012with3 Reads
DOI: 10.1016/j.ccr.2012.07.012 · Source: PubMed
Abstract
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.
    • "Whereas the fusion gene produces a 210-kDa protein in CML patients, the majority of pediatric ALL patients carry a 190-kDa protein; adult ALL patients may have either form [3]. Both proteins have constitutive tyrosine kinase activity increasing cell proliferation and inhibiting cell differentiation [2 @BULLET@BULLET ]. The presence of a BCR–ABL1 gene fusion is considered a poor prognostic indicator in pediatric and adult ALL patients with a high risk of relapse [21, 22]. Schultz et al. [23] showed that a combination of intensive imatinib dosing and intensive chemotherapy improved the 3-year event-free survival rate for children with minimal toxicity as compared to either imatinib or conventional chemotherapy alone. "
    [Show abstract] [Hide abstract] 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 (http://cgap.nci.nih.gov/Chromosomes/Mitelman). 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).
    Full-text · Article · Jun 2013
  • [Show abstract] [Hide abstract] 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.
    Article · May 2015
  • [Show abstract] [Hide abstract] ABSTRACT: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) arises from recurrent genetic insults that block precursor B-cell differentiation and drive aberrant proliferation and cell survival. Risk-adapted intensive chemotherapy is effective in curing the majority of children with BCP-ALL (>85%), but some children, not considered as "high-risk" and treated accordingly, will experience a hematological relapse. Moreover, survival rates in adults are significantly lower (∼40%) than those in children. Recent developments in genome-wide genetic analysis have provided a wide range of chromosomal and genomic abnormalities characterizing BCP-ALL, several of which are associated with patient outcome. These findings yield the opportunity to adapt risk stratification and treatment schedules and to identify new drugable targets. In this review we discuss the established and novel genetic alterations in BCP-ALL, their molecular background and potential use in risk stratification and treatment of BCP-ALL. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Article · Jun 2015

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