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A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.
Hungate EA, Vora SR, Gamazon ER, Moriyama T, Best T, Hulur I, Lee Y, Evans TJ, Ellinghaus E, Stanulla M, Rudant J, Orsi L, Clavel J, Milne E, Scott RJ, Pui CH, Cox NJ, Loh ML, Yang JJ, Skol AD, Onel K
(2016) Nat Commun 7: 10635
MeSH Terms: African Americans, Case-Control Studies, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 9, Cyclin-Dependent Kinase Inhibitor p15, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hispanic Americans, Humans, Infant, Male, Polymorphism, Single Nucleotide, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Show Abstract · Added February 22, 2016
Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10(-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.
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2 Members
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18 MeSH Terms
Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination.
Huye LE, Nakazawa Y, Patel MP, Yvon E, Sun J, Savoldo B, Wilson MH, Dotti G, Rooney CM
(2011) Mol Ther 19: 2239-48
MeSH Terms: Animals, Antigens, CD19, Apoptosis, B-Lymphocytes, Blotting, Western, Burkitt Lymphoma, Cell Proliferation, Cells, Cultured, Combined Modality Therapy, Drug Resistance, Neoplasm, Female, Flow Cytometry, Humans, Immunosuppressive Agents, Interferon-gamma, Lymphocyte Activation, Mice, Mice, Inbred NOD, Mice, SCID, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, Sirolimus, T-Lymphocytes, TOR Serine-Threonine Kinases
Show Abstract · Added August 22, 2013
Despite activity as single agent cancer therapies, Rapamycin (rapa) and its rapalogs may have their greatest effects when combined with other therapeutic modalities. In addition to direct antitumor activity, rapalogs reverse multiple tumor-intrinsic immune evasion mechanisms. These should facilitate tumor-specific T cell activity, but since rapa directly inhibits effector T cells, this potential immune enhancement is lost. We hypothesized that if T cells were rendered resistant to rapa they could capitalize on its downregulation of tumor immune evasion. We therefore modified T cells with a rapa-resistant mutant of mTor, mTorRR, and directed them to B lymphomas by coexpressing a chimeric antigen receptor (CAR) for CD19 (CAR.CD19-28ζ). T cells expressing transgenic mTorRR from a piggyBac transposon maintain mTor signaling, proliferate in the presence of rapa and retain their cytotoxic function and ability to secrete interferon-γ (IFNγ) after stimulation, effector functions that were inhibited by rapa in control T cells. In combination, rapa and rapa-resistant-CAR.CD19-28ζ-expressing T cells produced greater antitumor activity against Burkitt's lymphoma and pre-B ALL cell lines in vitro than CAR.CD19-28ζ T cells or rapa alone. In conclusion, the combination of rapa and rapa-resistant, CAR.CD19-28ζ-expressing T cells may provide a novel therapy for the treatment of B cell malignancies and other cancers.
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24 MeSH Terms
Racial differences in the survival of childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.
Pollock BH, DeBaun MR, Camitta BM, Shuster JJ, Ravindranath Y, Pullen DJ, Land VJ, Mahoney DH, Lauer SJ, Murphy SB
(2000) J Clin Oncol 18: 813-23
MeSH Terms: Adolescent, Adult, African Americans, African Continental Ancestry Group, Age Factors, Child, Child, Preschool, Cohort Studies, European Continental Ancestry Group, Female, Hispanic Americans, Humans, Infant, Leukocyte Count, Male, Ploidies, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Proportional Hazards Models, Sex Factors, Survival Rate, Treatment Outcome, United States
Show Abstract · Added November 27, 2013
PURPOSE - We conducted a historic cohort study to test the hypothesis that, after adjustment for biologic factors, African-American (AA) children and Spanish surname (SS) children with newly diagnosed B-precursor acute lymphoblastic leukemia had lower survival than did comparable white children.
PATIENTS AND METHODS - From 1981 to 1994, 4,061 white, 518 AA, and 507 SS children aged 1 to 20 years were treated on three successive Pediatric Oncology Group multicenter randomized clinical trials.
RESULTS - AA and SS patients were more likely to have adverse prognostic features at diagnosis and lower survival than were white patients. The 5-year cumulative survival rates were (probability +/- SE) 81.9% +/- 0.6%, 68.6% +/- 2.1%, and 74.9% +/- 2.0% for white, AA, and SS children, respectively. Adjusting for age, leukocyte count, sex, era of treatment, and leukemia blast cell ploidy, we found that AA children had a 42% excess mortality rate compared with white children (proportional hazards ratio [PHR] = 1.42; 95% confidence interval [CI], 1.12 to 1. 80), and SS children had a 33% excess mortality rate compared with white children (PHR = 1.33; 95% CI, 1.19 to 1.49).
CONCLUSION - Clinical presentation, tumor biology, and deviations from prescribed therapy did not explain the differences in survival and event-free survival that we observed, although differences seem to be diminishing over time with improvements in therapy. The disparity in outcome for AA and SS children is most likely related to variations in chemotherapeutic response to therapy and not to compliance. Further improvements in outcome may require individualized dosing based on specific pharmacogenetic profiles, especially for AA and SS children.
1 Communities
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24 MeSH Terms
Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.
Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM
(1998) Genes Dev 12: 1415-24
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Bone Marrow, Cysteine Endopeptidases, Cytoskeletal Proteins, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Homeodomain Proteins, Humans, Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Multienzyme Complexes, Neoplasm Proteins, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins pp60(c-src), Tumor Cells, Cultured, Ubiquitins, ras Proteins
Show Abstract · Added March 11, 2014
Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.
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22 MeSH Terms