Functional genomic landscape of acute myeloid leukaemia

Tyner, Jeffrey W.; Tognon, Cristina E.; Bottomly, Daniel; Wilmot, Beth; Kurtz, Stephen E.; Savage, Samantha L.; Long, Nicola; Schultz, Anna Reister; Traer, Elie; Abel, Melissa L.; Agarwal, Anupriya; Blucher, Aurora; Borate, Uma; Bryant, Jade; Burke, Russell T.; Carlos, Amy S.; Carpenter, Richie; Carroll, Joseph; Chang, Bill H.; Coblentz, Cody; d’Almeida, Amanda; Cook, Rachel J.; Danilov, Alexey V.; Dao, Kim; Degnin, Michie; DeVine, Deirdre; Dibb, James; Edwards, David K.; Eide, Christopher A.; English, Isabel; Glover, Jason; Henson, Rachel; Ho, Hibery; Jemal, Abdusebur; Johnson, Kara; Johnson, Ryan C.; Junio, Brian; Kaempf, Andy; Leonard, Jessica; Lin, Chenwei; Liu, Selina Qiuying; Lo, Pierrette; Loriaux, Marc; Luty, Samuel B.; Macey, Tara A.; MacManiman, Jason D.; Martinez, Jacqueline; Mori, Motomi; Nelson, Dylan; Nichols, Ceilidh; Peters, Jill; Ramsdill, Justin W; Rofelty, Angela; Schuff, Robert; Searles, Robert P.; Segerdell, Erik; Smith, Rebecca L.; Spurgeon, Stephen E.; Sweeney, Tyler; Thapa, Aashis; Visser, Corinne; Wagner, Jesse; Watanabe-Smith, Kevin; Werth, Kristen; Wolf, Joelle; White, Libbey; Yates, Amy; Zhang, Haijiao; Cogle, Christopher R.; Collins, Robert H.; Connolly, Denise C.; Deininger, Michael W.; Drusbosky, Leylah; Hourigan, Christopher S.; Jordan, Craig T.; Kropf, Patricia; Lin, Tara L.; Martinez, Micaela; Medeiros, Bruno C.; Pallapati, Rachel R.; Pollyea, Daniel A.; Swords, Ronan; Watts, Justin M.; Weir, Scott J.; Wiest, David L.; Winters, Ryan M.; McWeeney, Shannon K.; Druker, Brian J.

doi:10.1038/s41586-018-0623-z

Cited by 1,051 publications

(1,242 citation statements)

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“…To the best of our knowledge, the impact of VAF for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations has not been evaluated extensively previously. 19 Therapeutic agents targeting ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations might be necessary for improved outcome. The TP53 VAF was the major driver for worse survival as demonstrated on multivariate analysis, which demonstrated that each increasing increment in the VAF percentage was associated with a 1% higher risk of death.…”

Section: Discussionmentioning

confidence: 99%

“…21 The BEAT AML program reported on ex vivo drug sensitivity analyses and demonstrated that currently available targeted therapy could not target ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, except for several potential agents that target DNMT3A mutations. 19 Therapeutic agents targeting ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations might be necessary for improved outcome.…”

Section: Discussionmentioning

confidence: 99%

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Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Sasaki

Kanagal‐Shamanna

Montalban‐Bravo

et al. 2019

Cancer

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BACKGROUND:The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). METHODS: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. RESULTS: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. CONCLUSIONS: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML. Cancer 2020;126:765-774.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Sasaki

Kanagal‐Shamanna

Montalban‐Bravo

et al. 2019

Cancer

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“…33 A most recent gene profiling work performed with uncultured and untreated samples presented a large functional genomic data set of primary AML bone marrow mononuclear cells and revealed new markers and mechanisms of drug sensitivity and resistance. 6 Additionally, the ex vivo drug testing of 122 small molecule inhibitors was done in 2D culture for a short duration of 4 days and did not include Ara-C. There is about 20% overlap in mutated genes identified from this study compared to ours, indicating genetic markers predicting common drug responsiveness.…”

Section: Discussionmentioning

confidence: 80%

“…APP ranks 19 in our top 100 gene list for predicting Ara‐C responsiveness and was reported to be one of the potential candidate pathway genes of relevance for pharmacogenetic studies on ara‐C and other nucleoside analogs . A most recent gene profiling work performed with uncultured and untreated samples presented a large functional genomic data set of primary AML bone marrow mononuclear cells and revealed new markers and mechanisms of drug sensitivity and resistance . Additionally, the ex vivo drug testing of 122 small molecule inhibitors was done in 2D culture for a short duration of 4 days and did not include Ara‐C.…”

Section: Discussionmentioning

confidence: 99%

“…Selection of appropriate patients for clinical trials has been a challenging task, and researchers have been constantly searching for genetic biomarkers and gene signatures that can be used to predict drug responsiveness by whole-exome sequencing (WES) and RNAseq technologies. 4,6 Drug responsiveness was usually evaluated in 2D ex vivo culture during short-term treatment of 2-4 days using viability assay, which is considerably shorter than the duration of chemotherapy in the clinic that lasts ten days per cycle. 1 The 2D culture has been recognized for a long time as an insufficient system to accurately predict drug responsiveness due to the lack of physiologically relevant microenvironment.…”

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confidence: 99%

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Identification of predictive genetic signatures of Cytarabine responsiveness using a 3D acute myeloid leukaemia model

Muise

Javaid

et al. 2019

J Cellular Molecular Medi

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This study reports the establishment of a bone marrow mononuclear cell (BMMC) 3D culture model and the application of this model to define sensitivity and resistance biomarkers of acute myeloid leukaemia (AML) patient bone marrow samples in response to Cytarabine (Ara‐C) treatment. By mimicking physiological bone marrow microenvironment, the growth conditions were optimized by using frozen BMMCs derived from healthy donors. Healthy BMMCs are capable of differentiating into major hematopoietic lineages and various types of stromal cells in this platform. Cryopreserved BMMC samples from 49 AML patients were characterized for ex vivo growth and sensitivity to Ara‐C. RNA sequencing was performed for 3D and 2D cultures to determine differential gene expression patterns. Specific genetic mutations and/or gene expression signatures associated with the ability of the ex vivo expansion and response to Ara‐C were elucidated by whole‐exome and RNA sequencing. Data analysis identified unique gene expression signatures and novel genetic mutations associated with sensitivity to Ara‐C treatment of proliferating AML specimens and can be used as predictive therapeutic biomarkers to determine the optimal treatment regimens. Furthermore, these data demonstrate the translational value of this ex vivo platform which should be widely applicable to evaluate other therapies in AML.

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DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant

Dillon

Gui

Page

et al. 2023

JAMA

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ImportancePreventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized.ObjectiveTo determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants.Design, Setting, and ParticipantsIn this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research.ExposureCentralized DNA sequencing of banked pretransplant remission blood samples.Main Outcomes and MeasuresThe primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models.ResultsOf 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P &lt; .001) and decreased survival at 3 years (39% vs 63%; difference, −24% [2-sided 95% CI, −39% to −9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P &lt; .001).Conclusions and RelevanceAmong patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

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Functional genomic landscape of acute myeloid leukaemia

Cited by 1,051 publications

References 82 publications

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Identification of predictive genetic signatures of Cytarabine responsiveness using a 3D acute myeloid leukaemia model

DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant

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