Publications by authors named "Deedra Nicolet"

46 Publications

Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance).

Blood Adv 2021 Nov 30. Epub 2021 Nov 30.

The Ohio State University, United States.

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.
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http://dx.doi.org/10.1182/bloodadvances.2021006242DOI Listing
November 2021

Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.

Haematologica 2021 Jul 15. Epub 2021 Jul 15.

The Ohio State University, Comprehensive Cancer Center, Columbus.

Expression levels of long non-coding RNAs (lncRNAs) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNAs in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged.
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http://dx.doi.org/10.3324/haematol.2021.266643DOI Listing
July 2021

Precision oncology in AML: validation of the prognostic value of the knowledge bank approach and suggestions for improvement.

J Hematol Oncol 2021 07 6;14(1):107. Epub 2021 Jul 6.

The Ohio State University Comprehensive Cancer Center, 460 West 12th Avenue, Columbus, OH, 43210-1228, USA.

Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUC = 0.799), and both younger (< 60 years) (AUC = 0.747) and older patients (AUC = 0.770). The KB algorithm predicted non-remission death (AUC = 0.860) well but was less accurate in predicting relapse death (AUC = 0.695) and death in first complete remission (AUC = 0.603). The KB algorithm's 3-year OS predictive value was higher than that of the 2017 European LeukemiaNet (ELN) classification (AUC = 0.707, p < 0.001) and 2010 ELN classification (AUC = 0.721, p < 0.001) but did not differ significantly from that of the 17-gene stemness score (AUC = 0.732, p = 0.10). Analysis of additional cytogenetic and molecular markers not included in the KB algorithm revealed that taking into account atypical complex karyotype, infrequent recurrent balanced chromosome rearrangements and mutational status of the SAMHD1, AXL and NOTCH1 genes may improve the KB algorithm. We conclude that the KB algorithm has a high predictive value that is higher than those of the 2017 and 2010 ELN classifications. Inclusion of additional genetic features might refine the KB algorithm.
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http://dx.doi.org/10.1186/s13045-021-01118-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261916PMC
July 2021

A precision medicine classification for treatment of acute myeloid leukemia in older patients.

J Hematol Oncol 2021 06 23;14(1):96. Epub 2021 Jun 23.

The Ohio State University Comprehensive Cancer Center, 320 West 10th Avenue, Starling Loving Hall B302, Columbus, OH, 43210, USA.

Background: Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.

Methods: We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.

Results: Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17-42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.

Conclusions: By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
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http://dx.doi.org/10.1186/s13045-021-01110-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220739PMC
June 2021

Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq.

Leukemia 2021 12 21;35(12):3406-3420. Epub 2021 May 21.

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

Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
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http://dx.doi.org/10.1038/s41375-021-01295-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606012PMC
December 2021

Gene expression signature predicts relapse in adult patients with cytogenetically normal acute myeloid leukemia.

Blood Adv 2021 03;5(5):1474-1482

The Ohio State University Comprehensive Cancer Center, Columbus OH.

Although ∼80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), more than half of them relapse. Better identification of patients who are likely to relapse can help to inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML who were younger than 60 years of age and achieved a CR after induction treatment with standard "7+3" chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact outcome (ie, CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature that was strongly predictive of patient relapse (area under the receiver operating characteristics curve [AUC], 0.81). The signature consisted of 7 coding genes (GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55) and 3 long noncoding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P < .001), after adjustment for the FLT3-ITD, CEBPA, and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature's strong predictive value, with AUC = 0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients who are likely to relapse.
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http://dx.doi.org/10.1182/bloodadvances.2020003727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948288PMC
March 2021

Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia.

Cancer Discov 2021 03 4;11(3):626-637. Epub 2020 Dec 4.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients <60 years, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival. Gene mutation profiles showed fewer and more mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by mutations and -ITD, but, in contrast to White patients, was not improved by mutations. SIGNIFICANCE: We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933110PMC
March 2021

Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/.

Proc Natl Acad Sci U S A 2020 10 5;117(42):26340-26346. Epub 2020 Oct 5.

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.

Balanced rearrangements involving the gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/ rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/ rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/ rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/ rearrangements with material for molecular studies available. Patients with 11q23/ rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (, , and ) in 32% of patients. mutations occurred more often in patients with t(6;11)(q27;q23)/- compared with patients with the other 11q23/ subsets. Specific gene mutations were too infrequent in patients with specific 11q23/ rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/- had better outcomes than patients with other 11q23/ rearrangements and those without 11q23/ rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/ rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.
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http://dx.doi.org/10.1073/pnas.2014732117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584992PMC
October 2020

Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years.

Leukemia 2020 12 27;34(12):3215-3227. Epub 2020 May 27.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

The European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) have become an important tool to assess patients' prognosis and guide treatment. We tested the prognostic impact of the 2017 ELN classification in a large cohort of 863 AML patients aged <60 years similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. Based on multivariable models within each ELN genetic-risk group, we identified additional gene mutations that may refine the 2017 ELN risk classification. BCOR- or SETBP1-mutated favorable-risk patients with non-core-binding factor AML and IDH-mutated adverse-risk patients had intermediate-risk outcomes. Outcomes of NPM1/WT1 co-mutated patients and those of ZRSR2-mutated patients resembled outcome of adverse-risk patients. Moreover, FLT3-ITD allelic ratio conferred adverse rather than intermediate-risk irrespective of the NPM1 mutation status, and DNMT3A mutations associated with very poor survival. Application of these refinements reclassified 9% of current favorable-risk patients and 53% of current intermediate-risk patients to the adverse-risk group, with similar poor survival as current adverse-risk patients. Furthermore, 4% of current favorable-risk patients and 9% of adverse-risk patients were reclassified to the intermediate-risk group.
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http://dx.doi.org/10.1038/s41375-020-0872-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882079PMC
December 2020

Clinical and functional significance of circular RNAs in cytogenetically normal AML.

Blood Adv 2020 01;4(2):239-251

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18-60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression-based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation-related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML.
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http://dx.doi.org/10.1182/bloodadvances.2019000568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988408PMC
January 2020

The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.

Nat Commun 2019 11 25;10(1):5351. Epub 2019 Nov 25.

Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.
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http://dx.doi.org/10.1038/s41467-019-13259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877618PMC
November 2019

Clinical and molecular characterization of patients with acute myeloid leukemia and sole trisomies of chromosomes 4, 8, 11, 13 or 21.

Leukemia 2020 02 28;34(2):358-368. Epub 2019 Aug 28.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

Sole trisomies of chromosomes 4, 8, 11, 13 and 21 account for 89-95% of all sole trisomies in adult AML patients. We analyzed clinical and molecular characteristics of 138 de novo AML patients with sole +4, +8, +11, +13 or +21, and compared them with AML patients with those trisomies occurring in addition to other chromosome abnormalities (non-sole trisomy) and with cytogenetically normal AML (CN-AML) patients. Mutations in methylation-related genes were most commonly observed within each sole trisomy group (+4, 55%; +8, 58%; +11, 71%; +13, 71%; +21, 75% of patients). Patients with sole trisomies, excluding +4, also had frequent mutations in spliceosome genes (+8, 43%; +11, 65%; +13, 65%; +21, 45% of patients). In contrast, +4 patients frequently had mutations in transcription factor genes (44%) and NPM1 (36%). While 48% of patients with sole trisomies harbored mutations in a spliceosome gene, spliceosome mutations were observed in only 24% of non-sole trisomy (n = 131, P < 0.001) and 19% of CN-AML patients (n = 716, P < 0.001). Our data suggest that mutations affecting methylation-related genes are a molecular hallmark of sole trisomies. Mutations in spliceosome genes were also commonly observed in many sole trisomy patients and represent a novel finding in this cytogenetic subgroup.
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http://dx.doi.org/10.1038/s41375-019-0560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995758PMC
February 2020

Mutations associated with a 17-gene leukemia stem cell score and the score's prognostic relevance in the context of the European LeukemiaNet classification of acute myeloid leukemia.

Haematologica 2020 03 14;105(3):721-729. Epub 2019 Aug 14.

The Ohio State University Comprehensive Cancer Center, Columbus, OH

Leukemia stem cells (LSC) are more resistant to standard chemotherapy and their persistence during remission can cause relapse, which is still one of the major clinical challenges in the treatment of acute myeloid leukemia (AML). A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients' outcomes. We applied a previously described 17-gene expression score comprising genes differently expressed between LSC and leukemic bulk blasts, for 934 adult patients with AML, and studied associations of the 17-gene LSC score with clinical data and mutation status of 81 genes recurrently mutated in cancer and leukemia. We found that patients with a high 17-gene score were older and had more mutations. The 17-gene score was found to have a prognostic impact in both younger (aged <60 years) and older (aged ≥60 years) patients with AML. We also analyzed the 17-gene LSC score in the context of the 2017 European LeukemiaNet genetic-risk classification and found that for younger patients the score refined the classification, and identified patients currently classified in the European LeukemiaNet Favorable-risk category who had a worse outcome.
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http://dx.doi.org/10.3324/haematol.2019.225003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049376PMC
March 2020

Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia.

Clin Cancer Res 2019 11 2;25(21):6524-6531. Epub 2019 Aug 2.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Purpose: Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML. We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.

Results: We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with -internal tandem duplication (-ITD; < 0.001), and 11p UPD with mutations ( = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including -ITD and mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.

Conclusions: LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825549PMC
November 2019

Prognostic and Biologic Relevance of Clinically Applicable Long Noncoding RNA Profiling in Older Patients with Cytogenetically Normal Acute Myeloid Leukemia.

Mol Cancer Ther 2019 08 4;18(8):1451-1459. Epub 2019 Jun 4.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

We have previously shown that expression levels of 48 long noncoding RNAs (lncRNA) can generate a prognostic lncRNA score that independently associates with outcome of older patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the techniques used to identify and measure prognostic lncRNAs (i.e., RNA sequencing and microarrays) are not tailored for clinical testing. Herein, we report on an assay (based on the nCounter platform) that is designed to produce targeted measurements of prognostic lncRNAs in a clinically applicable manner. We analyzed a new cohort of 76 older patients with CN-AML and found that the nCounter assay yielded reproducible measurements and that the lncRNA score retained its prognostic value; patients with high lncRNA scores had lower complete remission (CR) rates ( = 0.009; 58% vs. 87%), shorter disease-free ( = 0.05; 3-year rates: 0% vs. 21%), overall (OS; = 0.02, 3-year rates: 10% vs. 29%), and event-free survival (EFS; = 0.002, 3-year rates: 0% vs. 18%) than patients with low lncRNA scores. In multivariable analyses, the lncRNA score independently associated with CR rates ( = 0.02), OS ( = 0.02), and EFS ( = 0.02). To gain biological insights, we examined our initial cohort of 71 older patients with CN-AML, previously analyzed with RNA sequencing. Genes involved in immune response and B-cell receptor signaling were enriched in patients with high lncRNA scores. We conclude that clinically applicable lncRNA profiling is feasible and potentially useful for risk stratification of older patients with CN-AML. Furthermore, we identify potentially targetable molecular pathways that are active in the high-risk patients with high lncRNA scores.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677601PMC
August 2019

Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically.

Leukemia 2019 07 8;33(7):1620-1634. Epub 2019 Feb 8.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Complex karyotype (CK) with ≥ 3 abnormalities is detected in 10-12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q, and/or 17p chromosome arms. The presence of 5q, 7q, and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥ 3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥ 1 balanced abnormality in addition to ≥ 2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations. They were younger (P = 0.007), had higher WBC (P = 0.001) and percentages of marrow (P < 0.001) and blood (P = 0.006) blasts, higher complete remission rates (P = 0.02), and longer overall survival (P < 0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.
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http://dx.doi.org/10.1038/s41375-019-0390-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609457PMC
July 2019

Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission.

Blood Adv 2018 07;2(13):1645-1650

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged <60 years, and 944 aged ≥60 years) enrolled in Cancer and Leukemia Group B treatment protocols and the cytogenetics companion protocol 8461 between 1983 and 2004. At 10 years, 267 (16.6%) of patients aged <60 years and 23 (2.4%) of those aged ≥60 years were alive and disease-free. This disease-free AML group consisted predominantly of patients with core-binding factor AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) and those with a normal karyotype. Occurrences of AML beyond 10 years were infrequent and associated with cytogenetic findings different from those at diagnosis. These data provide evidence that the frequency of long-term cure of AML is low among younger and especially older patients in the absence of Allo-HCT in CR1. In older patients not appropriate for Allo-HCT, these data provide further justification for early use of alternative treatments outside of intensive chemotherapy.
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http://dx.doi.org/10.1182/bloodadvances.2017015222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039651PMC
July 2018

NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome.

Leukemia 2018 12 5;32(12):2536-2545. Epub 2018 Jun 5.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was found in 27% of AML patients with NF1 mutations. NF1-mutated patients belonged more often to the adverse European LeukemiaNet (ELN) risk category than NF1 wild-type patients. Among patients aged <60 years, the presence of NF1 Thr676 mutations was associated with lower complete remission (CR) rates (P = 0.04) and shorter overall survival (OS; P = 0.01), as was the presence of any NF1 mutation in patients in the adverse ELN risk category (CR, P = 0.05; OS, P < 0.001). CR rates were also lower in NF1-mutated patients aged ≥60 years compared with NF1 wild-type patients (P = 0.001). In summary, our findings provide novel insights into the frequency of NF1 mutations in AML, and are suggestive of an adverse prognostic impact in patients treated with standard chemotherapy.
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http://dx.doi.org/10.1038/s41375-018-0147-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281863PMC
December 2018

Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies.

Leukemia 2018 06 25;32(6):1338-1348. Epub 2018 Feb 25.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Thus far, only 5-15% of AML patients aged ≥60 years are cured with chemotherapy. Identification of patients who are less (more) likely to respond to standard chemotherapy might enable early risk stratification toward alternative treatment regimens. We used a next-generation sequencing panel of 80 cancer- and/or leukemia-associated genes to profile molecularly 423 older patients with de novo AML. Using variables identified in multivariable models and co-occurring mutations in NPM1-mutated AML, we classified the patients into good-, intermediate-, and poor-risk groups for complete remission (CR) attainment, disease-free (DFS), and overall survival (OS). Whereas 81% of good-risk patients (comprising NPM1-mutated patients harboring mutations in chromatin remodeling, cohesin complex, methylation-related, spliceosome, and/or RAS pathway genes, FLT3-TKD, and/or patients without FLT3-ITD) achieved a CR, only 32% of poor-risk patients (with U2AF1, WT1 mutations and/or complex karyotype) did. Intermediate-risk patients had a 50% CR rate. Similarly, using NPM1 co-mutation patterns and SF1 mutation status, we identified patients with favorable DFS and OS 3-year rates of 46% and 45%, respectively. Patients with adverse genetic features had DFS and OS rates of only 2% and 4%. We show that application of our proposed criteria may refine the 2017 European LeukemiaNet classification for older patients treated with chemotherapy.
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http://dx.doi.org/10.1038/s41375-018-0068-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992022PMC
June 2018

Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia.

Oncotarget 2018 Jan 12;9(4):4354-4365. Epub 2017 Dec 12.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients ( = 61/303; 20%) with respect to age, sex and race matched controls ( = 43/402:11%, < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target and , both known miR-29 targets.
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http://dx.doi.org/10.18632/oncotarget.23150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796978PMC
January 2018

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia.

Proc Natl Acad Sci U S A 2017 06 22;114(23):E4641-E4647. Epub 2017 May 22.

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;

Epithelial growth factor-like 7 (EGFL7) is a protein that is secreted by endothelial cells and plays an important role in angiogenesis. Although EGFL7 is aberrantly overexpressed in solid tumors, its role in leukemia has not been evaluated. Here, we report that levels of both mRNA and EGFL7 protein are increased in blasts of patients with acute myeloid leukemia (AML) compared with normal bone marrow cells. High mRNA expression associates with lower complete remission rates, and shorter event-free and overall survival in older (age ≥60 y) and younger (age <60 y) patients with cytogenetically normal AML. We further show that AML blasts secrete EGFL7 protein and that higher levels of EGFL7 protein are found in the sera from AML patients than in sera from healthy controls. Treatment of patient AML blasts with recombinant EGFL7 in vitro leads to increases in leukemic blast cell growth and levels of phosphorylated AKT. EGFL7 blockade with an anti-EGFL7 antibody reduced the growth potential and viability of AML cells. Our findings demonstrate that increased EGFL7 expression and secretion is an autocrine mechanism supporting growth of leukemic blasts in patients with AML.
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http://dx.doi.org/10.1073/pnas.1703142114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468639PMC
June 2017

Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia.

Haematologica 2017 08 4;102(8):1391-1400. Epub 2017 May 4.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

Long non-coding ribonucleic acids (RNAs) are a novel class of RNA molecules, which are increasingly recognized as important molecular players in solid and hematologic malignancies. Herein we investigated whether long non-coding RNA expression is associated with clinical and molecular features, as well as outcome of younger adults (aged <60 years) with cytogenetically normal acute myeloid leukemia. Whole transcriptome profiling was performed in a training (n=263) and a validation set (n=114). Using the training set, we identified 24 long non-coding RNAs associated with event-free survival. Linear combination of the weighted expression values of these transcripts yielded a prognostic score. In the validation set, patients with high scores had shorter disease-free (<0.001), overall (=0.002) and event-free survival (<0.001) than patients with low scores. In multivariable analyses, long non-coding RNA score status was an independent prognostic marker for disease-free (=0.01) and event-free survival (=0.002), and showed a trend for overall survival (=0.06). Among multiple molecular alterations tested, which are prognostic in cytogenetically normal acute myeloid leukemia, only double mutations, mutations and -ITD associated with distinct long non-coding RNA signatures. Correlation of the long non-coding RNA scores with messenger RNA and microRNA expression identified enrichment of genes involved in lymphocyte/leukocyte activation, inflammation and apoptosis in patients with high scores. We conclude that long non-coding RNA profiling provides meaningful prognostic information in younger adults with cytogenetically normal acute myeloid leukemia. In addition, expression of prognostic long non-coding RNAs associates with oncogenic molecular pathways in this disease. .
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http://dx.doi.org/10.3324/haematol.2017.166215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541873PMC
August 2017

Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation.

Am J Hematol 2017 Apr 21;92(4):388-396. Epub 2017 Feb 21.

Department of Hematology, Oncology and Hemostaseology, University of Leipzig, Leipzig, Germany.

In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed.
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http://dx.doi.org/10.1002/ajh.24663DOI Listing
April 2017

Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality.

Cancer Res 2017 01 26;77(1):207-218. Epub 2016 Oct 26.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had less mutations in the methylation and spliceosome groups compared with patients ≥60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207-18. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215102PMC
January 2017

Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia.

Br J Haematol 2016 Oct 1;175(2):226-236. Epub 2016 Aug 1.

Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre-treatment DNMT3A R882 and all other AML-associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease-free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease-free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML-associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063708PMC
http://dx.doi.org/10.1111/bjh.14254DOI Listing
October 2016
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