Publications by authors named "Colton Smith"

36 Publications

Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity.

Clin Pharmacol Ther 2021 Mar 26. Epub 2021 Mar 26.

Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children's Research Hospital's Total XVI (TXVI, n = 598) and Children's Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0 × 10 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r  = 0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9 × 10 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.
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http://dx.doi.org/10.1002/cpt.2241DOI Listing
March 2021

Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks.

Leukemia 2021 Mar 13. Epub 2021 Mar 13.

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children's Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory networks impact ALL biology and contribute to transcriptomic differences among ALL subtypes.
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http://dx.doi.org/10.1038/s41375-021-01209-1DOI Listing
March 2021

Functional Outcome After Minimally Invasive Endoscopic Evacuation of Thalamic Intracerebral Hemorrhage.

World Neurosurg 2021 May 3;149:e592-e599. Epub 2021 Feb 3.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Intracerebral hemorrhage (ICH) is the most devastating form of stroke, with thalamic hemorrhages carrying the worst outcomes. Minimally invasive (MIS) endoscopic ICH evacuation is a promising new therapy for the condition. However, it remains unclear whether therapy success is location dependent. Here we present long-term functional outcomes after MIS evacuation of spontaneous thalamic hemorrhages.

Methods: Patients presenting to a single urban health system with spontaneous ICH were triaged to a central hospital for management of ICH. Operative criteria for MIS evacuation included hemorrhage volume ≥15 mL, age ≥18, National Institutes of Health Stroke Scale ≥6, and baseline modified Rankin Score (mRS) ≤3. Demographic, radiographic, and clinical data were collected prospectively, and descriptive statistics were performed retrospectively. Functional outcomes were assessed using 6-month mRS scores.

Results: Endoscopic ICH evacuation was performed on 21 patients. Eleven patients had hemorrhage confined to the thalamus, whereas 10 patients had hemorrhages in the thalamus and surrounding structures. Eighteen patients (85.7%) had intraventricular extension. The average preoperative volume was 39.8 mL (standard deviation [SD]: 31.5 mL) and postoperative volume was 3.8 mL (SD: 6.1 mL), resulting in an average evacuation rate of 91.4% (SD: 11.1%). One month after hemorrhage, 2 patients (9.5%) had expired and all other patients remained functionally dependent (90.5%). At 6-month follow-up, 4 patients (19.0%) had improved to a favorable outcome (mRS ≤ 3).

Conclusion: Among patients with ICH undergoing medical management, those with thalamic hemorrhages have especially poor outcomes. This study suggests that MIS evacuation can be safely performed in a thalamic population. It also presents long-term functional outcomes that can aid in planning randomization schemes or subgroup analyses in future MIS evacuation clinical trials.
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http://dx.doi.org/10.1016/j.wneu.2021.01.128DOI Listing
May 2021

Pharmacogenomics of intracellular methotrexate polyglutamates in patients' leukemia cells in vivo.

J Clin Invest 2020 12;130(12):6600-6615

Hematological Malignancies Program, and.

BACKGROUNDInterpatient differences in the accumulation of methotrexate's active polyglutamylated metabolites (MTXPGs) in leukemia cells influence its antileukemic effects.METHODSTo identify genomic and epigenomic and patient variables determining the intracellular accumulation of MTXPGs, we measured intracellular MTXPG levels in acute lymphoblastic leukemia (ALL) cells from 388 newly diagnosed patients after in vivo high-dose methotrexate (HDMTX) (1 g/m2) treatment, defined ALL subtypes, and assessed genomic and epigenomic variants influencing folate pathway genes (mRNA, miRNA, copy number alterations [CNAs], SNPs, single nucleotide variants [SNVs], CpG methylation).RESULTSWe documented greater than 100-fold differences in MTXPG levels, which influenced its antileukemic effects (P = 4 × 10-5). Three ALL subtypes had lower MTXPG levels (T cell ALL [T-ALL] and B cell ALL [B-ALL] with the TCF3-PBX1 or ETV6-RUNX1 fusions), and 2 subtypes had higher MTXPG levels (hyperdiploid and BCR-ABL like). The folate pathway genes SLC19A1, ABCC1, ABCC4, FPGS, and MTHFD1 significantly influenced intracellular MTXPG levels (P = 2.9 × 10-3 to 3.7 × 10-8). A multivariable model including the ALL subtype (P = 1.1 × 10-14), the SLC19A1/(ABCC1 + ABCC4) transporter ratio (P = 3.6 × 10-4), the MTX infusion time (P = 1.5 × 10-3), FPGS mRNA expression (P = 2.1 × 10-3), and MTX systemic clearance (P = 4.4 × 10-2) explained 42% of the variation in MTXPG accumulation (P = 1.1 × 10-38). Model simulations indicated that a longer infusion time (24 h vs. 4 h) was superior in achieving higher intracellular MTXPG levels across all subtypes if ALL.CONCLUSIONSThese findings provide insights into mechanisms underlying interpatient differences in intracellular accumulation of MTXPG in leukemia cells and its antileukemic effectsFUNDINGTHE National Cancer Institute (NCI) and the Institute of General Medical Sciences of the NIH, the Basque Government Programa Posdoctoral de Perfeccionamiento de Personal Investigador doctor, and the American Lebanese Syrian Associated Charities (ALSAC).
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http://dx.doi.org/10.1172/JCI140797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685728PMC
December 2020

Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.

Clin Pharmacol Ther 2020 Oct 29. Epub 2020 Oct 29.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition.
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http://dx.doi.org/10.1002/cpt.2095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081740PMC
October 2020

Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.

Nat Cancer 2020 Mar 9;1(3):329-344. Epub 2020 Mar 9.

Division of Hematology and Department of Internal Medicine, Mayo Clinic., Rochester, Minnesota, USA.

Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.
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http://dx.doi.org/10.1038/s43018-020-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467080PMC
March 2020

Massively parallel variant characterization identifies alleles associated with thiopurine toxicity.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5394-5401. Epub 2020 Feb 24.

Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, deficiency was identified as a genetic cause of thiopurine toxicity, and -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
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http://dx.doi.org/10.1073/pnas.1915680117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071893PMC
March 2020

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 01 14;67(1):e28040. Epub 2019 Oct 14.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI).

Procedure: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded.

Results: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4).

Conclusion: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.
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http://dx.doi.org/10.1002/pbc.28040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868303PMC
January 2020

Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge.

J Clin Oncol 2019 08 12;37(23):2051-2061. Epub 2019 Jun 12.

1St Jude Children's Research Hospital, Memphis, TN.

Purpose: Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.

Patients And Methods: PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.

Results: Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; = 1.4 × 10). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions ( = 2.4 × 10), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance ( = 5.0 × 10). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP ( = .0078) and was predicted by the occurrence of angioedema with first reaction ( = .01).

Conclusion: Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
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http://dx.doi.org/10.1200/JCO.18.02439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804844PMC
August 2019

FOXP2 exhibits projection neuron class specific expression, but is not required for multiple aspects of cortical histogenesis.

Elife 2019 05 17;8. Epub 2019 May 17.

Department of Pediatrics and Program in Developmental Neuroscience and Neurogenetics, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, United States.

The expression patterns of the transcription factor FOXP2 in the developing mammalian forebrain have been described, and some studies have tested the role of this protein in the development and function of specific forebrain circuits by diverse methods and in multiple species. Clinically, mutations in are associated with severe developmental speech disturbances, and molecular studies indicate that impairment of may lead to dysregulation of genes involved in forebrain histogenesis. Here, anatomical and molecular phenotypes of the cortical neuron populations that express FOXP2 were characterized in mice. Additionally, was removed from the developing mouse cortex at different prenatal ages using two Cre-recombinase driver lines. Detailed molecular and circuit analyses were undertaken to identify potential disruptions of development. Surprisingly, the results demonstrate that function is not required for many functions that it has been proposed to regulate, and therefore plays a more limited role in cortical development than previously thought.
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http://dx.doi.org/10.7554/eLife.42012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561705PMC
May 2019

Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children.

J Natl Cancer Inst 2019 12;111(12):1350-1357

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.

Methods: We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.

Results: A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10-8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.

Conclusions: These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
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http://dx.doi.org/10.1093/jnci/djz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910193PMC
December 2019

Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

Pediatr Blood Cancer 2019 06 13;66(6):e27669. Epub 2019 Feb 13.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated.

Procedure: Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy.

Results: We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS.

Conclusions: These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.
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http://dx.doi.org/10.1002/pbc.27669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472979PMC
June 2019

Novel susceptibility variants at the locus for childhood acute lymphoblastic leukemia in Hispanics.

Blood 2019 02 3;133(7):724-729. Epub 2018 Dec 3.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the gene (rs2836365; = 3.76 × 10; odds ratio [OR] = 1.56), with independent validation ( = .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the risk variant rose with increasing Native American genetic ancestry. The risk genotype was underrepresented in ALL with the fusion ( < .0005) but enriched in the subtype ( < .05). Interestingly, ALL cases with germline risk alleles were significantly less likely to have somatic deletion ( < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.
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http://dx.doi.org/10.1182/blood-2018-07-862946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376278PMC
February 2019

Genetics of pleiotropic effects of dexamethasone.

Pharmacogenet Genomics 2017 08;27(8):294-302

Departments of aPharmaceutical Sciences bBiostatistics cOncology dComprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

Objectives: Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia.

Patients And Methods: We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low-density lipoproteins after dexamethasone.

Results: The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46×10(-215), and these variants were more likely to be in gene-regulatory regions (P=1.22×10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions.

Conclusion: The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects.
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http://dx.doi.org/10.1097/FPC.0000000000000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523978PMC
August 2017

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

Cancer 2017 Sep 11;123(18):3602-3608. Epub 2017 May 11.

Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown.

Methods: A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate.

Results: Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10 ).

Conclusions: These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589497PMC
September 2017

Osteonecrosis is unrelated to hip anatomy in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2017 Jul 30;64(7). Epub 2016 Dec 30.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee.

Osteonecrosis is a debilitating toxicity associated with acute lymphoblastic leukemia (ALL) treatment. A recent report associated interindividual differences in hip anatomy with the development of idiopathic osteonecrosis in adults. To evaluate the impact of hip anatomy on the development of therapy-related osteonecrosis, we retrospectively evaluated the femoral neck-shaft angle, femoral neck offset, and lateral center-edge angle using x-rays of 18 osteonecrosis cases and 46 control children treated for newly diagnosed ALL on a single protocol. Despite adequate statistical power, we found no association between hip anatomy and osteonecrosis. Investigation of other factors contributing to ALL-associated osteonecrosis is warranted.
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http://dx.doi.org/10.1002/pbc.26407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596390PMC
July 2017

The impact of the UGT1A1*60 allele on bilirubin serum concentrations.

Pharmacogenomics 2017 Jan 14;18(1):5-16. Epub 2016 Dec 14.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Aim: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant.

Materials & Methods: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants.

Results: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients.

Conclusion: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.
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http://dx.doi.org/10.2217/pgs-2016-0135DOI Listing
January 2017

Lizards fail to plastically adjust nesting behavior or thermal tolerance as needed to buffer populations from climate warming.

Glob Chang Biol 2017 03 9;23(3):1075-1084. Epub 2016 Sep 9.

Department of Biology, University of Washington, Seattle, WA, 98125, USA.

Although observations suggest the potential for phenotypic plasticity to allow adaptive responses to climate change, few experiments have assessed that potential. Modeling suggests that Sceloporus tristichus lizards will need increased nest depth, shade cover, or embryonic thermal tolerance to avoid reproductive failure resulting from climate change. To test for such plasticity, we experimentally examined how maternal temperatures affect nesting behavior and embryonic thermal sensitivity. The temperature regime that females experienced while gravid did not affect nesting behavior, but warmer temperatures at the time of nesting reduced nest depth. Additionally, embryos from heat-stressed mothers displayed increased sensitivity to high-temperature exposure. Simulations suggest that critically low temperatures, rather than high temperatures, historically limit development of our study population. Thus, the plasticity needed to buffer this population has not been under selection. Plasticity will likely fail to compensate for ongoing climate change when such change results in novel stressors.
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http://dx.doi.org/10.1111/gcb.13476DOI Listing
March 2017

Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.

J Clin Oncol 2016 06 25;34(18):2133-40. Epub 2016 Apr 25.

Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified.

Methods: To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors.

Results: Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10(-9)). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation.

Conclusion: Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.
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http://dx.doi.org/10.1200/JCO.2015.64.5812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962704PMC
June 2016

Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.

Blood 2016 Feb 20;127(5):558-64. Epub 2015 Nov 20.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 × 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 × 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.
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http://dx.doi.org/10.1182/blood-2015-10-673848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742546PMC
February 2016

Resolving the life cycle alters expected impacts of climate change.

Proc Biol Sci 2015 Aug;282(1813):20150837

School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.

Recent models predict contrasting impacts of climate change on tropical and temperate species, but these models ignore how environmental stress and organismal tolerance change during the life cycle. For example, geographical ranges and extinction risks have been inferred from thermal constraints on activity during the adult stage. Yet, most animals pass through a sessile embryonic stage before reaching adulthood, making them more susceptible to warming climates than current models would suggest. By projecting microclimates at high spatio-temporal resolution and measuring thermal tolerances of embryos, we developed a life cycle model of population dynamics for North American lizards. Our analyses show that previous models dramatically underestimate the demographic impacts of climate change. A predicted loss of fitness in 2% of the USA by 2100 became 35% when considering embryonic performance in response to hourly fluctuations in soil temperature. Most lethal events would have been overlooked if we had ignored thermal stress during embryonic development or had averaged temperatures over time. Therefore, accurate forecasts require detailed knowledge of environmental conditions and thermal tolerances throughout the life cycle.
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http://dx.doi.org/10.1098/rspb.2015.0837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632613PMC
August 2015

Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia.

Blood 2015 Oct 11;126(15):1770-6. Epub 2015 Aug 11.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;

Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 × 10(-7)). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio [OR] = 1.87 and 2.26; P = .063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 × 10(-8)), and the glutamate pathway was the top ranked pathway (P = 9.8 × 10(-4)). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 × 10(-3)), and arterial embolism and thrombosis (OR = 1.88; P = 4.2 × 10(-3)). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.
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http://dx.doi.org/10.1182/blood-2015-05-643601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600016PMC
October 2015

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.

Blood 2015 Jul 18;126(1):69-75. Epub 2015 May 18.

Department of Pharmaceutical Sciences, and.

Asparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a genome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children's Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 × 10(-8); odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH ALL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 × 10(-3) and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 × 10(-6); OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response.
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http://dx.doi.org/10.1182/blood-2015-02-628800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492197PMC
July 2015

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.

Nat Genet 2015 Jun 4;47(6):607-14. Epub 2015 May 4.

1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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.
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http://dx.doi.org/10.1038/ng.3283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449308PMC
June 2015

Oxygen supply limits the heat tolerance of lizard embryos.

Biol Lett 2015 Apr;11(4):20150113

Department of Physiology, Midwestern University, Glendale, AZ 85308, USA.

The mechanisms that set the thermal limits to life remain uncertain. Classically, researchers thought that heating kills by disrupting the structures of proteins or membranes, but an alternative hypothesis focuses on the demand for oxygen relative to its supply. We evaluated this alternative hypothesis by comparing the lethal temperature for lizard embryos developing at oxygen concentrations of 10-30%. Embryos exposed to normoxia and hyperoxia survived to higher temperatures than those exposed to hypoxia, suggesting that oxygen limitation sets the thermal maximum. As all animals pass through an embryonic stage where respiratory and cardiovascular systems must develop, oxygen limitation may limit the thermal niches of terrestrial animals as well as aquatic ones.
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http://dx.doi.org/10.1098/rsbl.2015.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424623PMC
April 2015

Effect of premedications in a murine model of asparaginase hypersensitivity.

J Pharmacol Exp Ther 2015 Mar 8;352(3):541-51. Epub 2015 Jan 8.

Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.)

A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Sensitized mice had complete inhibition of plasma asparaginase activity (P = 4.2 × 10(-13)) and elevated levels of mouse mast cell protease 1 (P = 6.1 × 10(-3)) compared with nonsensitized mice. We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor (PAF) receptor antagonist CV-6209 [2-(2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl)-1-ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. Combining triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity compared with nonpretreated, sensitized mice (P = 1.2 × 10(-5)). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P = 0.03) and partially restoring asparaginase activity (P = 8.3 × 10(-4)). To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice. Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell-derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity.
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http://dx.doi.org/10.1124/jpet.114.220780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352598PMC
March 2015

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

Blood 2015 Jan 2;125(4):680-6. Epub 2014 Dec 2.

Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA;

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. 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 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.
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http://dx.doi.org/10.1182/blood-2014-09-595744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304112PMC
January 2015

HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.

Blood 2014 Aug 26;124(8):1266-76. Epub 2014 Jun 26.

Department of Pharmaceutical Sciences, and.

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 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 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 × 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.
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http://dx.doi.org/10.1182/blood-2014-03-563742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141516PMC
August 2014