title: Targeting signaling pathways in acute lymphoblastic leukemia: new insights.
abstract: The genetics of acute lymphoblastic leukemia are becoming well understood and the incidence of individual chromosomal abnormalities varies considerably with age. Cytogenetics provide reliable risk stratification for treatment: high hyperdiploidy and ETV6-RUNX1 are good risk, whereas BCR-ABL1, MLL rearrangements, and hypodiploidy are poor risk. Nevertheless, some patients within the good- and intermediate-risk groups will unpredictably relapse. With advancing technologies in array-based approaches (single nucleotide polymorphism arrays) and next-generation sequencing to study the genome, increasing numbers of new genetic changes are being discovered. These include deletions of B-cell differentiation and cell cycle control genes, as well as mutations of genes in key signaling pathways. Their associations and interactions with established cytogenetic subgroups and with each other are becoming elucidated. Whether they have a link to outcome is the most important factor for refinement of risk factors in relation to clinical trials. For several newly identified abnormalities, including intrachromosomal amplification of chromosome 21 (iAMP21), that are associated with a poor prognosis with standard therapy, appropriately modified treatment has significantly improved outcome. After the successful use of tyrosine kinase inhibitors in the treatment of BCR-ABL1-positive acute lymphoblastic leukemia, patients with alternative ABL1 translocations and rearrangements involving PDGFRB may benefit from treatment with tyrosine kinase inhibitors. Other aberrations, for example, CRLF2 overexpression and JAK2 mutations, are also providing potential novel therapeutic targets with the prospect of reduced toxicity.
authors: 1Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
authors: Christine J
authors: CJ
authors: Harrison
mesh_terms: D002869:Chromosome Aberrations; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016044:Fusion Proteins, bcr-abl; D011495:Histone-Lysine N-Methyltransferase; D053614:Janus Kinase 2; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D020797:Receptor, Platelet-Derived Growth Factor beta; D018121:Receptors, Cytokine; C581634:BCR-ABL1 fusion protein, human; C498762:CRLF2 protein, human; C497422:KMT2A protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C507924:JAK2 protein, human