PMID- 24970932
OWN - NLM
STAT- MEDLINE
DCOM- 20141015
LR  - 20211021
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 124
IP  - 8
DP  - 2014 Aug 21
TI  - HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.
PG  - 1266-76
LID - 10.1182/blood-2014-03-563742 [doi]
AB  - Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with 
      immune responses resulting in suboptimal drug exposure and a greater risk of 
      relapse. To elucidate whether there is a genetic component to the mechanism of 
      asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) 
      alleles in patients of European ancestry enrolled on leukemia trials at St. Jude 
      Children's Research Hospital (n = 541) and the Children's Oncology Group (n = 
      1329). We identified a higher incidence of hypersensitivity and anti-asparaginase 
      antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 x 10(-5), odds ratio 
      [OR] = 1.64; P = 1.4 x 10(-5), OR = 2.92, respectively). Structural analysis 
      revealed that high-risk amino acids were located within the binding pocket of the 
      HLA protein, possibly affecting the interaction between asparaginase epitopes and 
      the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the 
      binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients 
      whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 x 
      10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 
      alleles that confer high-affinity binding to asparaginase epitopes lead to a 
      higher frequency of reactions. These trials were registered at 
      www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.
CI  - (c) 2014 by The American Society of Hematology.
FAU - Fernandez, Christian A
AU  - Fernandez CA
AD  - Department of Pharmaceutical Sciences, and.
FAU - Smith, Colton
AU  - Smith C
AD  - Department of Pharmaceutical Sciences, and.
FAU - Yang, Wenjian
AU  - Yang W
AD  - Department of Pharmaceutical Sciences, and.
FAU - Date, Mihir
AU  - Date M
AD  - Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, 
      TN;
FAU - Bashford, Donald
AU  - Bashford D
AD  - Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, 
      TN;
FAU - Larsen, Eric
AU  - Larsen E
AD  - Maine Children's Cancer Program, Scarborough, ME;
FAU - Bowman, W Paul
AU  - Bowman WP
AD  - Department of Hematology and Oncology, Cook Children's Medical Center, Fort 
      Worth, TX;
FAU - Liu, Chengcheng
AU  - Liu C
AD  - Department of Pharmaceutical Sciences, and.
FAU - Ramsey, Laura B
AU  - Ramsey LB
AD  - Department of Pharmaceutical Sciences, and.
FAU - Chang, Tamara
AU  - Chang T
AD  - Department of Pharmaceutical Sciences, and.
FAU - Turner, Victoria
AU  - Turner V
AD  - Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
FAU - Loh, Mignon L
AU  - Loh ML
AD  - Department of Pediatrics, University of California School of Medicine, San 
      Francisco, CA;
FAU - Raetz, Elizabeth A
AU  - Raetz EA
AD  - Department of Pediatrics, New York University Medical Center, NY;
FAU - Winick, Naomi J
AU  - Winick NJ
AD  - University of Texas Southwestern Medical Center, Dallas, TX;
FAU - Hunger, Stephen P
AU  - Hunger SP
AD  - Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation and Center 
      for Cancer and Blood Disorders, University of Colorado Denver School of Medicine, 
      Children's Hospital Colorado, Aurora, CO;
FAU - Carroll, William L
AU  - Carroll WL
AD  - Department of Pediatrics, New York University Medical Center, NY;
FAU - Onengut-Gumuscu, Suna
AU  - Onengut-Gumuscu S
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
FAU - Chen, Wei-Min
AU  - Chen WM
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
FAU - Concannon, Patrick
AU  - Concannon P
AD  - Genetics Institute, University of Florida, Gainesville, FL;
FAU - Rich, Stephen S
AU  - Rich SS
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
FAU - Scheet, Paul
AU  - Scheet P
AD  - Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, 
      Houston, TX;
FAU - Jeha, Sima
AU  - Jeha S
AD  - Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN; and.
FAU - Pui, Ching-Hon
AU  - Pui CH
AD  - Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN; and.
FAU - Evans, William E
AU  - Evans WE
AD  - Department of Pharmaceutical Sciences, and.
FAU - Devidas, Meenakshi
AU  - Devidas M
AD  - Department of Biostatistics, College of Medicine, University of Florida, 
      Gainesville, FL.
FAU - Relling, Mary V
AU  - Relling MV
AD  - Department of Pharmaceutical Sciences, and.
LA  - eng
SI  - PDB/3PDO
SI  - ClinicalTrials.gov/NCT00137111
SI  - ClinicalTrials.gov/NCT00549848
SI  - ClinicalTrials.gov/NCT00005603
SI  - ClinicalTrials.gov/NCT00075725
GR  - GM92666/GM/NIGMS NIH HHS/United States
GR  - CA 142665/CA/NCI NIH HHS/United States
GR  - CA98543/CA/NCI NIH HHS/United States
GR  - CA 36401/CA/NCI NIH HHS/United States
GR  - R01 CA142665/CA/NCI NIH HHS/United States
GR  - CA114766/CA/NCI NIH HHS/United States
GR  - R37 CA036401/CA/NCI NIH HHS/United States
GR  - P30 CA021765/CA/NCI NIH HHS/United States
GR  - U10 CA098543/CA/NCI NIH HHS/United States
GR  - R01 CA036401/CA/NCI NIH HHS/United States
GR  - U10 CA180899/CA/NCI NIH HHS/United States
GR  - CA98413/CA/NCI NIH HHS/United States
GR  - U01 GM092666/GM/NIGMS NIH HHS/United States
GR  - U10 CA098413/CA/NCI NIH HHS/United States
GR  - U24 CA114766/CA/NCI NIH HHS/United States
GR  - CA 21765/CA/NCI NIH HHS/United States
GR  - U10 CA180886/CA/NCI NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140626
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Epitopes)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*07 antigen)
RN  - EC 3.5.1.1 (Asparaginase)
SB  - IM
CIN - Blood. 2014 Aug 21;124(8):1206-7. PMID: 25147374
MH  - Adolescent
MH  - Adult
MH  - *Alleles
MH  - *Antibodies/blood/immunology
MH  - Antineoplastic Agents/administration & dosage/*adverse effects
MH  - Asparaginase/administration & dosage/*adverse effects
MH  - Child
MH  - Child, Preschool
MH  - *Drug Hypersensitivity/blood/genetics/immunology
MH  - Epitopes/blood/genetics/immunology
MH  - Female
MH  - *HLA-DRB1 Chains/genetics/immunology
MH  - Humans
MH  - Infant
MH  - Leukemia/*drug therapy/genetics/immunology/pathology
MH  - Male
MH  - Risk Factors
PMC - PMC4141516
EDAT- 2014/06/28 06:00
MHDA- 2014/10/16 06:00
PMCR- 2015/08/21
CRDT- 2014/06/28 06:00
PHST- 2014/06/28 06:00 [entrez]
PHST- 2014/06/28 06:00 [pubmed]
PHST- 2014/10/16 06:00 [medline]
PHST- 2015/08/21 00:00 [pmc-release]
AID - S0006-4971(20)39803-7 [pii]
AID - 2014/563742 [pii]
AID - 10.1182/blood-2014-03-563742 [doi]
PST - ppublish
SO  - Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 
      Jun 26.