Currently we test and support the following browsers:
Please note that this is not intended to be an exhaustive list of browsers that support web standards, nor a test of browser compliance, nor a side-by-side comparison of various manufacturers’ browsers.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and despite generally favorable treatment outcomes, it remains a leading cause of death among pediatric patients with cancer. ALL has long been characterized by gross chromosomal alterations, including gains and losses of whole chromosomes and translocations of chromosomal segments.
Over the past several years, St. Jude researchers have identified many genetic alterations that cause leukemia and those that influence its treatment outcome. They have also characterized the nature of inherited genetic variations that influence the risk of leukemia. Here we describe three key studies completed last year that have extended these findings.
Ethnic differences that affect survival after childhood ALL are well recognized. Previous clinical studies have shown that patients of African American or Hispanic descent have poorer survival than those of European American or Asian descent, but the genetic basis for this variation has been poorly understood. Jun J. Yang, PhD (Pharmaceutical Sciences), and colleagues addressed this question by profiling genetic variations in more than 400,000 germline single nucleotide polymorphisms (SNPs) in 2,534 children with ALL from a diverse range of self-reported ethnic backgrounds, including Northern European, West African, East Asian, and Native American. This information was used to define the genetic ancestry of each individual.
In an article published in Nature Genetics1, the authors showed that Native American ancestry is associated with a high risk of leukemia relapse independent of established prognostic risk factors. Furthermore, the effect of ethnicity was reduced by administering an additional delayed course of intensive chemotherapy.
Dr. Yang’s team identified a polymorphism in the PDE4B gene that was associated with a high risk of ALL relapse. Leukemic cells expressing higher levels of PDE4B are more resistant to prednisolone, a drug widely used to treat ALL. This finding suggests a mechanism that links inherited genetic variation to treatment responsiveness in leukemia. The investigators concluded that adding an assessment of germline genomic variation to current ALL risk–stratification processes may be beneficial to pediatric patients with newly diagnosed ALL.
In a second study examining the genetic basis of ALL relapse, Charles G. Mullighan, MBBS (Hons), MSc, MD (Pathology), and colleagues performed detailed sequencing of more than 300 genes in samples of leukemic cells obtained from 23 pediatric patients with ALL. Samples were obtained at the time of diagnosis and again at the time of relapse to identify mutations associated with leukemia development and treatment failure.
Dr. Mullighan’s team reported their findings of multiple new targets of mutation in ALL in the journal Nature1. The gene that encodes CREB-binding protein, CREBBP, was mutated or deleted in almost 20% of cases of relapsed ALL but was rarely mutated in ALL cells obtained at diagnosis. Further testing showed that the mutations were either acquired after diagnosis or were present in a minor population of leukemic cells at diagnosis and were selected for during anticancer therapy.
CREBBP has multiple functions, including the regulation of transcription, epigenetic modification, and responsiveness to steroids. In collaboration with Paul K. Brindle, PhD (Biochemistry), Dr. Mullighan showed that the CREBBP mutations impaired cells’ normal response to glucocorticoids, suggesting another likely mechanism for leukemic cells to resist anticancer treatment. Drugs such as histone deacetylase inhibitors, which modulate the activity of CREBBP and other proteins, are being explored as a potential new therapeutic option for patients with relapsed leukemia.
In the third study, published in Nature Medicine1, William E. Evans, PharmD (Pharmaceutical Sciences), and colleagues determined the genomic cause and functional consequences of the inactivation of the DNA mismatch–repair enzyme MSH2 in primary human leukemia cells.
The investigators measured MSH2 mRNA and protein levels in 90 bone marrow aspirate samples obtained from patients at the time of ALL diagnosis. The leukemic cells from 10 (11%) children had low or undetectable MSH2 protein levels, despite having abundant MSH2 mRNA. Among 252 children treated on the St. Jude Total Therapy XV protocol, those whose ALL cells had low MSH2 protein levels had a lower rate of 10-year overall survival (78.7% vs 97.5%) and a higher incidence of hematologic relapse (20.6% vs 5.1%) than the remaining children. Furthermore, genomic profiling revealed that leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four of the following genes that regulate MSH2 degradation: FRAP1 (mTOR), HERC1, PRKCZ, and PIK32B.
Dr. Evans’ team showed that the absence of these genes recapitulates the MSH2 protein deficiency by enhancing MSH2 degradation, which reduces DNA-mismatch repair and increases resistance to the anticancer drugs mercaptopurine and thioguanine. These findings identified a new genomic mechanism by which leukemia cells acquire MSH2 deficiency and anticancer drug resistance.
1Yang JJ, Cheng C, Devidas M, Cao X, Fan Y, Campana D, Yang W, Neale G, Cox NJ, Scheet P, Borowitz MJ, Winick NJ, Martin PL, Willman CL, Bowman WP, Camitta BM, Carroll A, Reaman GH, Carroll WL, Loh M, Hunger SP, Pui CH, Evans WE, Relling MV. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet Mar;43(3):237-41, 2011. doi: 10.1038/ng.763. Epub 2011 Feb 6. PubMed PMID: 21297632; PubMed Central PMCID: PMC3104508. Abstract | Full Text
1Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, Heatley SL, Holmfeldt L, Collins-Underwood JR, Ma J, Buetow KH, Pui CH, Baker SD, Brindle PK, Downing JR. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature Mar 10;471(7337):235-9, 2011. PubMed PMID: 21390130; PubMed Central PMCID: PMC3076610. Abstract | Full Text
1Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen S, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV, Evans WE. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med Sep 25;17(10):1298-303, 2011. doi: 10.1038/nm.2430. PubMed PMID: 21946537; PubMed Central PMCID: PMC3192247. Abstract | Full Text