Faculty Bibliography
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338
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children
There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.
PMCID:4544058
PMID: 26104880
ISSN: 2041-1723
CID: 2927292
NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells
Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases.
PMCID:4449308
PMID: 25938942
ISSN: 1546-1718
CID: 1569082
Association of intravenous (IV) and intramuscular (IM) pegaspargase (PEG) administration with rate of adverse events (AE) in standard risk (SR) Acute Lymphoblastic Leukemia (ALL) Children's Oncology Group (COG) trials. [Meeting Abstract]
ISI:000358036900041
ISSN: 1527-7755
CID: 1729792
Feasibility of intensive post-Induction therapy incorporating clofarabine (CLOF) in the very high risk (VHR) stratum of patients with newly diagnosed high risk B-lymphoblastic leukemia (HR B-ALL): Children's Oncology Group AALL1131. [Meeting Abstract]
ISI:000358036900010
ISSN: 1527-7755
CID: 1729442
Outcomes of dasatinib plus intensive chemotherapy or stem cell transplant (SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) on Children's Oncology Group AALL0622. [Meeting Abstract]
ISI:000358036900009
ISSN: 1527-7755
CID: 1729432
Neurocognitive function of children treated for high-risk B-acute lymphoblastic leukemia (HR-ALL) randomized to Capizzi (CMTX) versus high-dose methotrexate (HDMTX): A report from the Children's Oncology Group (COG). [Meeting Abstract]
ISI:000358036900005
ISSN: 1527-7755
CID: 1729422
Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
PMCID:4377644
PMID: 25790293
ISSN: 2041-1723
CID: 1520792
Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. PROCEDURE: P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. RESULTS: We report an overall 5-year EFS and OS of 42.3 +/- 6% and 52.9 +/- 6.5% respectively. Poor prognostic factors included age /=50,000/mul. For infants 90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 +/- 8% for MLL-R versus 69.1 +/- 13.6% for MLL-germline ALL (P < 0.0001). CONCLUSIONS: Age
PMCID:5145261
PMID: 25399948
ISSN: 1545-5009
CID: 1477622
Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology Group
BACKGROUND:Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. PROCEDURE/METHODS:AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). RESULTS:Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012). CONCLUSION/CONCLUSIONS:De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.
PMCID:4480675
PMID: 25407157
ISSN: 1545-5017
CID: 2927322
A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults
Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA: 16-39 years) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. To better understand the disease etiology in this age group, we performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with European, African and Native American genetic ancestries as a covariates. SNPs that reached association P
PMCID:4304112
PMID: 25468567
ISSN: 0006-4971
CID: 1371022
