Publications by authors named "Tanja A Gruber"

35 Publications

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

Br J Haematol 2021 Feb 2. Epub 2021 Feb 2.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22 blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.
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http://dx.doi.org/10.1111/bjh.17333DOI Listing
February 2021

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML.

Cancers (Basel) 2020 Oct 17;12(10). Epub 2020 Oct 17.

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as , or are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.
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http://dx.doi.org/10.3390/cancers12103024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603219PMC
October 2020

Correction: A six-gene leukemic stem cell score identifies high risk pediatric acute myeloid leukemia.

Leukemia 2020 Oct;34(10):2821

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41375-020-0822-0DOI Listing
October 2020

Acute Megakaryoblastic Leukemia with Trisomy 21 and Tetrasomy 21 Clones in a Phenotypically Normal Child with Mosaic Trisomy 21.

Case Rep Pediatr 2020 17;2020:7813048. Epub 2020 Mar 17.

Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.

Pediatric acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) that may be divided into two subgroups: (1) Down syndrome- (DS-) related AMKL which generally has a favorable prognosis and (2) non-DS-related AMKL which generally has a poorer outcome. We report a phenotypically normal child with AMKL with trisomy 21 (T21) and tetrasomy 21 clones. Subsequently, she was diagnosed with mosaic T21. She underwent reduced-intensity therapy with good outcome. We review the literature regarding AMKL-associated cytogenetic abnormalities and AMKL in association with DS. We suggest evaluation for mosaic T21 in phenotypically normal pediatric patients with T21-positive AML.
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http://dx.doi.org/10.1155/2020/7813048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103042PMC
March 2020

Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.

Blood Adv 2019 11;3(21):3307-3321

Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.

Acute megakaryoblastic leukemia (AMKL) represents ∼10% of pediatric acute myeloid leukemia cases and typically affects young children (<3 years of age). It remains plagued with extremely poor treatment outcomes (<40% cure rates), mostly due to primary chemotherapy refractory disease and/or early relapse. Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A. Human models of NUP98-KDM5A-driven AMKL capable of faithfully recapitulating the disease have been lacking, and patient samples are rare, further limiting biomarkers and drug discovery. To overcome these impediments, we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and progenitor cells using a lentiviral-based approach to create physiopathologically relevant disease models. The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions. Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient mice led to multiple subtypes of leukemia, including AMKL, that phenocopy human disease phenotypically and molecularly. The integrative molecular characterization of synthetic and patient NUP98-KDM5A AMKL samples revealed SELP, MPIG6B, and NEO1 as distinctive and novel disease biomarkers. Transcriptomic and proteomic analyses pointed to upregulation of the JAK-STAT signaling pathway in the model AMKL. Both synthetic models and patient-derived xenografts of NUP98-rearranged AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically approved JAK2 inhibitor. Overall, synthetic human AMKL models contribute to defining functional dependencies of rare genotypes of high-fatality pediatric leukemia, which lack effective and rationally designed treatments.
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http://dx.doi.org/10.1182/bloodadvances.2019030981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855103PMC
November 2019

Replication timing alterations in leukemia affect clinically relevant chromosome domains.

Blood Adv 2019 11;3(21):3201-3213

Department of Biological Science, Florida State University, Tallahassee, FL.

Human B-cell precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed that BCP-ALL cells display unique and clonally heritable, stable DNA replication timing (RT) programs (ie, programs describing the variable order of replication and subnuclear 3D architecture of megabase-scale chromosomal units of DNA in different cell types). To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients with varied genetic subtypes and outcomes. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that seem to be associated with relapse. These results suggest that the genesis of BCP-ALL involves alterations in RT that reflect biologically significant and potentially clinically relevant leukemia-specific epigenetic changes.
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http://dx.doi.org/10.1182/bloodadvances.2019000641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855107PMC
November 2019

Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16.

J Clin Oncol 2019 12 28;37(35):3377-3391. Epub 2019 Oct 28.

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

Purpose: Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control.

Patients And Methods: Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m versus the conventional 2,500 U/m. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.

Results: The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] 5.7% [95% CI, 2.8% to 8.6%]; = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.

Conclusion: Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
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http://dx.doi.org/10.1200/JCO.19.01692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351342PMC
December 2019

A six-gene leukemic stem cell score identifies high risk pediatric acute myeloid leukemia.

Leukemia 2020 03 23;34(3):735-745. Epub 2019 Oct 23.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Recently, mRNA-expression signature enriched in LSCs was used to create a 17-gene leukemic stem cell (LSC17) score predictive of prognosis in adult AML. By fitting a Cox-LASSO regression model to the clinical outcome and gene-expression levels of LSC enriched genes in 163 pediatric participants of the AML02 multi-center clinical trial (NCT00136084), we developed a six-gene LSC score of prognostic value in pediatric AML (pLSC6). In the AML02 cohort, the 5-year event-free survival (EFS) of patients within low-pLSC6 group (n = 97) was 78.3 (95% CI = 70.5-86.9%) as compared with 34.5(95% CI = 24.7-48.2 %) in patients within high-pLSC6 group (n = 66 subjects), p < 0.00001. pLSC6 remained significantly associated with EFS and overall survival (OS) after adjusting for induction 1-MRD status, risk-group, FLT3-status, WBC-count at diagnosis and age. pLSC6 formula developed in the AML02 cohort was validated in the pediatric AML-TARGET project data (n = 205), confirming its prognostic value in both single-predictor and multiple-predictor Cox regression models. In both cohorts, pLSC6 predicted outcome of transplant patients, suggesting it as a useful criterion for transplant referrals. Our results suggest that pLSC6 score holds promise in redefining initial risk-stratification and identifying poor risk AML thereby providing guidance for developing novel treatment strategies.
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http://dx.doi.org/10.1038/s41375-019-0604-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135934PMC
March 2020

Single-Cell RNA Sequencing Reveals a Developmental Hierarchy in Langerhans Cell Histiocytosis.

Authors:
Tanja A Gruber

Cancer Discov 2019 Oct;9(10):1343-1345

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

In this issue of , Halbritter and colleagues utilize single-cell RNA sequencing to dissect the cellular hierarchy in Langerhans cell histiocytosis. They identified a remarkably consistent composition of 14 cellular subsets across all patients with a range of clinical spectrums consistent with a shared developmental hierarchy driven by key transcriptional regulators..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0820DOI Listing
October 2019

Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies.

Clin Cancer Res 2019 12 27;25(24):7320-7330. Epub 2019 Aug 27.

Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Purpose: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.

Patients And Methods: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.

Results: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f ( = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f ( = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f ( < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent ( = 0.0015) but not with sequential ( = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib ( = 0.0004) and sorafenib N-oxide ( = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.

Conclusions: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911639PMC
December 2019

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3-ITD AML.

Clin Transl Sci 2019 11 20;12(6):641-647. Epub 2019 Aug 20.

Division of Pharmaceutics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3-ITD+ AML. Using RNA sequencing and a next-generation targeted gene panel, we broadly characterize the co-occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3-ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0-3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3-ITD+ AML and could help stratify future targeted treatment strategies.
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http://dx.doi.org/10.1111/cts.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853146PMC
November 2019

A tale of two genes: a new connection between and in acute myeloid leukemia.

Haematologica 2019 07;104(7):1289-1291

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

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http://dx.doi.org/10.3324/haematol.2019.218867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601087PMC
July 2019

Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.

Nat Commun 2019 06 26;10(1):2789. Epub 2019 Jun 26.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.
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http://dx.doi.org/10.1038/s41467-019-10637-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594946PMC
June 2019

A high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML.

Nat Commun 2019 05 16;10(1):2189. Epub 2019 May 16.

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.
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http://dx.doi.org/10.1038/s41467-019-09917-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522510PMC
May 2019

Clinical cancer genomic profiling by three-platform sequencing of whole genome, whole exome and transcriptome.

Nat Commun 2018 09 27;9(1):3962. Epub 2018 Sep 27.

Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

To evaluate the potential of an integrated clinical test to detect diverse classes of somatic and germline mutations relevant to pediatric oncology, we performed three-platform whole-genome (WGS), whole exome (WES) and transcriptome (RNA-Seq) sequencing of tumors and normal tissue from 78 pediatric cancer patients in a CLIA-certified, CAP-accredited laboratory. Our analysis pipeline achieves high accuracy by cross-validating variants between sequencing types, thereby removing the need for confirmatory testing, and facilitates comprehensive reporting in a clinically-relevant timeframe. Three-platform sequencing has a positive predictive value of 97-99, 99, and 91% for somatic SNVs, indels and structural variations, respectively, based on independent experimental verification of 15,225 variants. We report 240 pathogenic variants across all cases, including 84 of 86 known from previous diagnostic testing (98% sensitivity). Combined WES and RNA-Seq, the current standard for precision oncology, achieved only 78% sensitivity. These results emphasize the critical need for incorporating WGS in pediatric oncology testing.
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http://dx.doi.org/10.1038/s41467-018-06485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160438PMC
September 2018

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: a retrospective study by the I-BFM Study Group.

Blood 2018 10 27;132(15):1584-1592. Epub 2018 Aug 27.

Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands.

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. (n = 23) had significantly lower median white blood cell count (12.5 × 10/L, = .03) compared with the reference cohort. rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort ( = .004). Four-year event-free survival (EFS) of patients with was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, < .001). Four-year EFS of was 77% (SE = 8%, = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in , 0% (SE = 0%) in compared with 32% (SE = 1%) in the reference cohort ( < .001). Multivariate analysis identified both and as independent risk factors with hazard ratios of 1.9 ( < .0001) and 0.3 ( = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.
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http://dx.doi.org/10.1182/blood-2018-05-849059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265640PMC
October 2018

De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.

Nat Commun 2018 05 2;9(1):1770. Epub 2018 May 2.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.

Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 , FLT3 , and NRAS accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the Kras locus, consistent with a strong selective advantage of additional Kras . KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.
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http://dx.doi.org/10.1038/s41467-018-04180-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932012PMC
May 2018

NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.

Genes Chromosomes Cancer 2018 06 28;57(6):311-319. Epub 2018 Mar 28.

Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.

The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98-BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34 cells and in leukemic blasts, as with the fly BPTF homolog, Nurf301. Disease course was marked by rapid progression and primary chemoresistance, with ultimately significant tumor burden reduction following treatment with a clofarabine containing regimen. In sum, we report 2 novel NUP98-BPTF fusion isoforms that contribute to refine the NUP98r subgroup of pediatric AMKL. Multicenter clinical trials are critically required to determine the frequency of this fusion in AMKL patients and explore innovative treatment strategies for a disease still plagued with poor outcomes.
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http://dx.doi.org/10.1002/gcc.22532DOI Listing
June 2018

An unexpected protein interaction promotes drug resistance in leukemia.

Nat Commun 2017 11 16;8(1):1547. Epub 2017 Nov 16.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital (SJCRH), Memphis, TN, 38105, USA.

The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance. Specific disruption of this protein complex, either genetically or chemically, removed ABCC4 from the plasma membrane, increased drug sensitivity, and abrogated MPP1-dependent hematopoietic progenitor cell replating in methylcellulose. High-throughput screening identified Antimycin A as a small molecule that disrupted the ABCC4-MPP1 protein complex and reversed drug resistance in AML cell lines and in primary patient AML cells. In all, targeting the ABCC4-MPP1 protein complex can lead to new therapies to improve treatment outcome of AML, a disease where the long-term prognosis is poor.
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http://dx.doi.org/10.1038/s41467-017-01678-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691054PMC
November 2017

Central nervous system disease in pediatric acute myeloid leukemia.

Pediatr Blood Cancer 2017 12 29;64(12). Epub 2017 Aug 29.

Erasmus MC-Sophia, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1002/pbc.26782DOI Listing
December 2017

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues.

Cancer Res 2017 04 16;77(8):2102-2111. Epub 2017 Feb 16.

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.

Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2'deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419029PMC
April 2017

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.

Nat Genet 2017 Mar 23;49(3):451-456. Epub 2017 Jan 23.

Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.
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http://dx.doi.org/10.1038/ng.3772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687824PMC
March 2017

The genomic landscape of core-binding factor acute myeloid leukemias.

Nat Genet 2016 12 31;48(12):1551-1556. Epub 2016 Oct 31.

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

Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.
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http://dx.doi.org/10.1038/ng.3709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508996PMC
December 2016

Germline Mutations in Predisposition Genes in Pediatric Cancer.

N Engl J Med 2015 Dec 18;373(24):2336-2346. Epub 2015 Nov 18.

Departments of Computational Biology (J.Z., G.W., M.N.E., D.H., X.M., X.Z., M.R.W., X.C., M.R., A.P., J.B.B., S.W.), Oncology (M.F.W., T.A.G., R.B.M., S.H.-D., R.N., E.Q., A.G., A.S.P., C.-H.P., K.E.N.), and Pathology (T.A.G., M.R.W., S.A.S., D.W.E., C.-H.P., J.R.D.) and the Pediatric Cancer Genome Project (J.Z., M.F.W., G.W., M.N.E., T.A.G., J.E., X.M., D.A.Y., B.V., X.C., R.B.M., S.H.-D., R.N., E.Q., S.A.S., M.R., A.P., J.B.B., S.W., M.S.W., A.G., D.W.E., A.S.P., C.-H.P., K.E.N., J.R.D.), St. Jude Children's Research Hospital, Memphis, TN; and the Department of Genetics and McDonnell Genome Institute, Washington University School of Medicine in St. Louis, St. Louis (L.D., E.R.M., R.K.W.).

Background: The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.

Methods: In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).

Results: Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.

Conclusions: Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).
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http://dx.doi.org/10.1056/NEJMoa1508054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734119PMC
December 2015

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.

Cancer Discov 2016 Feb 13;6(2):154-65. Epub 2015 Nov 13.

Foundation Medicine, Cambridge, Massachusetts.

Unlabelled: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.

Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
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http://dx.doi.org/10.1158/2159-8290.CD-15-0913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744547PMC
February 2016

The biology of pediatric acute megakaryoblastic leukemia.

Blood 2015 Aug 17;126(8):943-9. Epub 2015 Jul 17.

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

Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of newly diagnosed pediatric acute myeloid leukemia patients. AMKL in children with Down syndrome (DS) is characterized by a founding GATA1 mutation that cooperates with trisomy 21, followed by the acquisition of additional somatic mutations. In contrast, non-DS-AMKL is characterized by chimeric oncogenes consisting of genes known to play a role in normal hematopoiesis. CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in this subset of patients and confers a poor prognosis.
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http://dx.doi.org/10.1182/blood-2015-05-567859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551356PMC
August 2015

Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.

Lancet Oncol 2015 Apr 20;16(4):465-74. Epub 2015 Mar 20.

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Background: The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions.

Methods: Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at ClinicalTrials.gov, number NCT00137111.

Findings: Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (69·2%, 95% CI 49·6-82·4, n=36 vs 95·5%, 91·7-97·5, n=244; p<0·001 for the provisional low-risk group and 65·1%, 50·7-76·2, n=56 vs 82·9%, 75·6-88·2, n=142; p=0·01 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<0·01%) on day 46 were treated for standard-risk ALL and had a 10-year event-free survival of 88·9% (43·3-98·4). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (72·7%, 42·5-88·8 vs 84·0%, 76·3-89·4; p=0·06) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.

Interpretation: Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease.

Funding: National Institutes of Health and American Lebanese Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1470-2045(15)70082-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612585PMC
April 2015