Showing papers by "Mignon L. Loh published in 2012"
St. Jude Children's Research Hospital1, Washington University in St. Louis2, Memorial Sloan Kettering Cancer Center3, Katholieke Universiteit Leuven4, University of California, San Francisco5, University of Toronto6, University of Padua7, University of Colorado Denver8, University of Florida9, Boston Children's Hospital10, University of New Mexico11, University of Virginia12
TL;DR: The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal andMyeloid leukaemia haematopoietic stem cells, suggesting that addition of myeloids-directed therapies might improve the poor outcome of E TP ALL.
Abstract: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.
1,425 citations
St. Jude Children's Research Hospital1, BC Cancer Agency2, University of New Mexico3, University of California, San Francisco4, National Institutes of Health5, Children's Hospital of Philadelphia6, New York University7, Memorial Sloan Kettering Cancer Center8, University of Texas MD Anderson Cancer Center9, University of Florida10, Children's National Medical Center11, University of Colorado Denver12, University of British Columbia13
TL;DR: Several genetic alterations that activate kinase signaling in Ph-like ALL induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
616 citations
TL;DR: Preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, are demonstrated and the therapeutic potential of targeted kinase inhibition in Ph-like ALL is highlighted.
269 citations
TL;DR: Next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders and lower the threshold of detection for MRD and affect treatment decisions.
Abstract: High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.
244 citations
TL;DR: The biochemical sequelae of CRLf2 and JAK alterations in CRLF2-rearranged ALL primary patient samples are characterized via analysis of TSLP-mediated signal transduction, suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials.
209 citations
Children's Oncology Group1, University of New Mexico2, St. Jude Children's Research Hospital3, Ohio State University4, Nationwide Children's Hospital5, Johns Hopkins University6, Medical College of Wisconsin7, University of Alabama at Birmingham8, University of Florida9, University of Mississippi Medical Center10, Children's Hospital of Philadelphia11, Children's National Medical Center12, Boston Children's Hospital13, New York University14, University of California, San Francisco15, University of Texas Southwestern Medical Center16, University of Colorado Denver17
TL;DR: High CRLF2 expression is associated with a very poor outcome in high-risk, but not standard- risk, ALL, and in multivariate analyses, NCI risk group, MRD, high CRLf2 expression, and IKZF1 lesions were associated with relapse-free survival.
207 citations
University of Florida1, University of Texas MD Anderson Cancer Center2, University of California, San Francisco3, National Institutes of Health4, University of Texas Southwestern Medical Center5, Duke University6, University of New Mexico7, Medical College of Wisconsin8, George Washington University9, New York University10, University of Colorado Denver11
TL;DR: ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
Abstract: Purpose Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome. Patients and Methods We compared the association between ARID5B SNP genotype and ALL susceptibility in whites ( 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics ( 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children’s Oncology Group (COG) P9904/9905 clinical trials.
161 citations
University of Florida1, University of Chicago2, University of Texas MD Anderson Cancer Center3, Johns Hopkins University4, University of Texas Southwestern Medical Center5, Duke University6, Medical College of Wisconsin7, George Washington University8, New York University9, University of New Mexico10, University of Colorado Denver11, University of California, San Francisco12
TL;DR: Host genetic variations related to treatment outcome of childhood ALL were systematically identified, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs.
106 citations
TL;DR: Recent advances in the understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children are outlined, and novel therapeutic approaches that are currently being tested in clinical trials are discussed.
Abstract: Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereas MPN is associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed.
46 citations
University of Florida1, University of British Columbia2, New York University3, University of Utah4, University of California, San Francisco5, Oregon Health & Science University6, Johns Hopkins University7, Harvard University8, Vanderbilt University9, University of Texas Southwestern Medical Center10, University of Alabama at Birmingham11, Ohio State University12, Seattle Cancer Care Alliance13, St. Jude Children's Research Hospital14, University of Colorado Boulder15
TL;DR: The safety and feasibility of continuous dasatinib (60 mg/m2) integrated with the intensive phases of the modified AALL0031 backbone was established and no induction deaths occurred in either cohort.
8 citations
Johns Hopkins University School of Medicine1, Children's Oncology Group2, University of Alabama at Birmingham3, Ohio State University4, University of California, San Francisco5, New York University6, Children's Medical Center of Dallas7, Boston Children's Hospital8, University of Colorado Denver9, Johns Hopkins University10
TL;DR: A safety/activity (S/A) phase to determine a safe and biologically active dose of lestaurtinib is reported and results of the S/A phase for HR pts are reported.
Abstract: 9548 Background: MLL-r infant ALL overexpresses activated FLT3. Lestaurtinib potentiates chemotherapy(chemo)-induced cytotoxicity in MLL-r ALL. AALL0631 therapy is stratified based on age and MLL s...
Baylor College of Medicine1, University of Utah2, New York University3, St. Jude Children's Research Hospital4, University of Florida5, University of Bologna6, University of Padua7, Institute of Cancer Research8, Newcastle University9, University of California, San Francisco10, University of Colorado Denver11
TL;DR: Children with Down syndrome have an increased risk of developing acute lymphoblastic leukemia (ALL), and consistently demonstrate poorer outcomes due to higher rates of both relapse and treatment-related mortality compared to other children with ALL, and this data helps improve risk stratification and identify potential novel therapeutic targets in this vulnerable population.
TL;DR: Both methods are rapid, highly effective and very comparable for finding ALL cases that harbor CRLF2 genomic lesions, and suitable for incorporation in large scale clinical trials.
TL;DR: It is hypothesized that inhibition of JAK/STAT and PI3K/mTOR phosphosignaling correlates with therapeutic responses in these models, and the creation of CRLF2r ALL xenograft models has enabled rapid preclinical testing of STIs and measurement of in vivo target inhibition.
Abstract: 9506 Background: Therapy intensification for children with B-precursor ALL with high-risk genetic lesions has improved relapse-free survival. CRLF2 rearrangements and JAK2 and IL7RA mutations occur...
TL;DR: A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in SLCO1B1 (p = 2.1 × 10 −11), a gene that encodes for an organic anion transporter that is known to transport methot Rexate.
TL;DR: Findings provide critical new insights into the genetic basis of hypodiploid ALL, and indicate that therapeutic targeting of the Ras pathway should be pursued in this disease.
Abstract: Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia characterized by multiple whole chromosomal losses and very dismal outcome. Our previous genome wide study of hypodiploid childhood ALL cases treated by the Children9s Oncology Group and St Jude, employed interrogation of DNA copy number alterations using Affymetrix SNP 6.0 microarrays, candidate gene resequencing and gene expression profiling using Affymetrix U133 Plus 2.0 microarrays. These analyses showed that this disease can be divided into multiple subtypes characterized by variation in the degree of aneuploidy, distinct submicroscopic deletions, sequence mutations and gene expression profile. Near haploid ALL (24-31 chromosomes) frequently harbors alterations of genes regulating Ras signaling (67.6%; NF1, NRAS, KRAS, PTPN11, FLT3, and PAG1), IKZF3 (encoding the lymphoid transcription factor AIOLOS; 13.2%), and a histone gene cluster at 6p22 (17.6%), while low hypodiploid ALL (32-39 chromosomes) is enriched for IKZF2 (HELIOS; 52.9%), TP53 (70.6%) and RB1 (41.2%) alterations. A striking finding was exclusivity of Ras signaling and IKZF2/3 alterations, and biochemical indications of Ras pathway activation in both near haploid and low hypodiploid ALL. To further interrogate the genomic changes of hypodiploid ALL, we performed next generation sequencing using either Illumina GAIIx or HiSeq3000 sequencers on both tumor and matched remission DNA. Whole genome sequencing to at least 30 fold haploid coverage was performed on 10 near haploid and 8 low hypodiploid cases, and whole exome sequencing (Agilent SureSelect Human All Exon 50Mb) on 5 near haploid and 1 low hypodiploid cases. The burden of single nucleotide variations (SNVs) and insertion/deletion (indel) mutations was in general low in this ALL subtype, with 0-5 indels and 9-95 SNVs in coding regions and untranslated leader regions in the whole genome sequenced cases, where the majority of cases had fewer than 30 SNVs. Further, the number of structural variations, including the ones too small to be identified by SNP microarray analysis, and structural rearrangements, were also low, with less than 25 structural variations identified in the whole genome sequenced cases. For the whole exomes, between 10 and 42 non-silent SNVs and 1-2 indels were identified per case. No recurrent alterations not previously identified in the hypodiploid cohort were found in these 24 cases, indicating that the initial genome wide study of this cohort identified the major recurrent alterations in hypodiploid ALL. However, the recurrence screening including the remaining 78 near haploid and low hypodiploid cases in our cohort on the alterations identified by the whole genome and exome sequencing study is ongoing. Altogether, these findings provide critical new insights into the genetic basis of hypodiploid ALL, and indicate that therapeutic targeting of the Ras pathway should be pursued in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4870. doi:1538-7445.AM2012-4870