Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level

Chen, Jiahao; Kao, Yun Ruei; Sun, Daqian; Todorova, Tihomira I.; Reynolds, David M.; Narayanagari, Swathi Rao; Montagna, Cristina; Will, Britta; Verma, Amit; Steidl, Ulrich

doi:10.1038/s41591-018-0267-4

Cited by 175 publications

(154 citation statements)

References 59 publications

(56 reference statements)

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“…In particular, it is likely to become increasingly important to determine which molecular alterations are occurring within the same disease clone—methods that rely on using both cytogenetic and sequencing‐based assays will not be able to address this challenge as effectively as comprehensive sequencing‐based methods. Single‐cell methods for assaying either DNA or RNA are currently being used to show the heterogeneity within patient samples . At present, these methods are too time‐consuming and costly for routine clinical application.…”

Section: How Should Patients Be Screened?mentioning

confidence: 99%

“…Single-cell methods for assaying either DNA or RNA are currently being used to show the heterogeneity within patient samples. [32][33][34] At present, these methods are too time-consuming and costly for routine clinical application. As single-cell genomic methods mature, and the impact of clonal heterogeneity on disease outcomes becomes more clear, these methods will likely have a large impact on clinical decision-making.…”

Section: Detection Of Molecular Alterations By Gene Panel Wes Wgs Ormentioning

confidence: 99%

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Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single‐gene testing to an era dominated by next‐generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome‐based testing may offer several distinct benefits beyond traditional DNA‐based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single‐gene tests to the era of NGS panels and genome‐wide sequencing—highlighting both the potential and drawbacks of these novel technologies.

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Section: How Should Patients Be Screened?mentioning

confidence: 99%

Section: Detection Of Molecular Alterations By Gene Panel Wes Wgs Ormentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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“…In support of the relevance of our modeling approach to human AML, we show extensive similarities of gene expression and chromatin accessibility between our iPSC-derived cells and primary human hematopoietic cells, establishing that SAR and SARF iPSC-HSPCs resemble leukemic stem/progenitor cells. While some recent studies have provided evidence of non-linear (parallel or branching) clonal evolution in some cases of sAML 8,34 , a linear clonal evolution scenario remains the more likely mode of evolution in the majority of sAML cases, and is thus the most relevant and best-suited to our modeling approach.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to most cancers, acute myeloid leukemia (AML) results from the sequential acquisition of driver mutations by the same hematopoietic stem/progenitor cell (HSPC) clone over time. Large-scale sequencing of tumor genomes of patients with AML, as well as individuals with clinically defined preleukemic conditions -myelodysplastic syndrome (MDS) and age-related clonal hematopoiesis (CH) -have yielded crucial information on the relative timing of acquisition of specific gene mutations 7,8 . More recently, sequencing of large AML patient cohorts revealed robust mutational cooperation patterns enabling inference of mutational paths 9 .…”

Section: Introductionmentioning

confidence: 99%

Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of leukemia

Wang

Pine

Wesely

et al. 2020

Preprint

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Human cancers arise through an evolutionary process whereby cells acquire somatic mutations that drive them to outgrow normal cells and create successive clonal populations. "Bottom-up" human cancer evolution models could help illuminate this process, but their creation has faced significant challenges. Here we combined human induced pluripotent stem cell (iPSC) and CRISPR/Cas9 technologies to develop a model of the clonal evolution of acute myeloid leukemia (

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“…Understanding the fundamental mechanisms of MPN predisposition may inform the development of novel preventive interventions for the disease, analogous to the implementation of human papillomavirus testing and colonoscopic surveillance to reduce cervical and colorectal cancer incidence, respectively 44,45 . In this context, modulation of HSC function or improved surveillance of this compartment may enable therapies to prevent progression to clonal hematopoietic disorders like MPNs [46][47][48] . More broadly, our findings may serve as a paradigm for dissecting the underlying basis of cancer predisposition alleles.…”

Section: Main Textmentioning

confidence: 99%

Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

Bao

Nandakumar

Liao

et al. 2019

Preprint

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3Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs) 1 . While substantial progress has been made to define the causal somatic mutation profile for MPNs 2 , epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers 3 . However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function. 4 Main Text:We initially sought to characterize the germline genetic architecture that confers risk for MPNs, and therefore conducted a genome-wide association study (GWAS) meta-analysis using three population-based cohorts (UK Biobank (UKBB), 23andMe, and FinnGen). The combined sample size comprised 2,627 MPN cases and 755,476 controls, more than doubling the number of cases from prior studies (Supplementary Table 1, Extended Data Fig. 1). We tested 7,329,649 well-represented variants passing central and studyspecific quality control measures. Linkage disequilibrium score regression (LDSC) 4 showed negligible inflation in test statistics due to population structure, with an intercept of 1.005 and genomic control factor of 1.0255. We estimate the narrow-sense heritability for MPN risk to be 0.0717 (s.e. = 0.0306) on the liability scale, suggesting that ~7% of variance in MPN risk can be attributed to common genetic variation (MAF > 1%), assuming a disease prevalence of 0.0328%, as reported in population studies 5,6 .Analysis of GWAS signals using GCTA 7 revealed 12 linkage disequilibrium (LD)independent loci at genome-wide significance (p < 5 x 10 -8 ) and an additional 16 loci with suggestive associations (p < 1 x 10 -6 ) ( Fig. 1a, Supplementary Table 2). Previous studies have shown that carriers of the somatic JAK2 V617...

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Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level

Cited by 175 publications

References 59 publications

Genomic testing in myeloid malignancy

Genomic testing in myeloid malignancy

Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of leukemia

Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

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