Faculty Opinions recommendation of Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes.

2019 ◽  
Author(s):  
Eirini Papapetrou ◽  
Tiansu Wang
Keyword(s):  
Myelodysplastic Syndromes ◽  
Clonal Evolution

scholarly journals Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3296
Author(s):  
Ioannis Chanias ◽  
Kristina Stojkov ◽  
Gregor Stehle ◽  
Michael Daskalakis ◽  
Helena Simeunovic ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Myelodysplastic Syndromes ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Future Perspectives ◽  
Hematopoietic Stem ◽  
Secondary Acute Myeloid Leukemia ◽  
Stem And Progenitor Cells ◽  
Unfit Patients ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

scholarly journals Pathophysiology of Myelodysplastic Syndromes

Hemato ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 477-495
Author(s):  
Michaela Fontenay ◽  
Batoul Farhat ◽  
Ismael Boussaid
Keyword(s):  
Myelodysplastic Syndromes ◽  
Tumor Response ◽  
Clonal Evolution ◽  
Epistatic Interactions ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Inflammatory State ◽  
Immune Contexture ◽  
Immunosuppressive Cells ◽  
Genetic Events

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

scholarly journals SNP array–based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6876-6884 ◽  
Author(s):  
Manuel G. Afable ◽  
Marcin Wlodarski ◽  
Hideki Makishima ◽  
Mohammed Shaik ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Immune Escape ◽  
Neutral Loss ◽  
Clonal Evolution ◽  
Snp Array ◽  
Single Nucleotide ◽  
Genomic Aberrations ◽  
Disease Entities ◽  
N 93

Abstract In aplastic anemia (AA), contraction of the stem cell pool may result in oligoclonality, while in myelodysplastic syndromes (MDS) a single hematopoietic clone often characterized by chromosomal aberrations expands and outcompetes normal stem cells. We analyzed patients with AA (N = 93) and hypocellular MDS (hMDS, N = 24) using single nucleotide polymorphism arrays (SNP-A) complementing routine cytogenetics. We hypothesized that clinically important cryptic clonal aberrations may exist in some patients with BM failure. Combined metaphase and SNP-A karyotyping improved detection of chromosomal lesions: 19% and 54% of AA and hMDS cases harbored clonal abnormalities including copy-neutral loss of heterozygosity (UPD, 7%). Remarkably, lesions involving the HLA locus suggestive of clonal immune escape were found in 3 of 93 patients with AA. In hMDS, additional clonal lesions were detected in 5 (36%) of 14 patients with normal/noninformative routine cytogenetics. In a subset of AA patients studied at presentation, persistent chromosomal genomic lesions were found in 10 of 33, suggesting that the initial diagnosis may have been hMDS. Similarly, using SNP-A, earlier clonal evolution was found in 4 of 7 AA patients followed serially. In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities.

Genetic Landscape and Clonal Evolution Following 5-Aza Therapy in Patients with High-Risk Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4304-4304
Author(s):  
June Takeda ◽  
Yusuke Shiozawa ◽  
Yuichi Shiraishi ◽  
Yusuke Okuno ◽  
Keisuke Kataoka ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Clonal Evolution ◽  
Clone Size ◽  
Chugai Pharmaceutical ◽  
Before And After ◽  
Targeted Capture ◽  
Post Therapy ◽  
Capture Sequencing

Abstract Background: DNA hypomethylating agents, such as 5-azacitidine (5-aza) and decitabine, comprise the current standard in therapy for patients with high-risk myelodysplastic syndromes (MDS), with dramatic responses in some patients. However, the responses are poorly predictable and their impact on clonal dynamics has not been fully elucidated. Patients and Methods: We enrolled a total of 119 patients with high-risk MDS who were treated with 5-aza . Bone marrow samples were collected before (n = 71) and both before and after (n = 48) treatment and analyzed by targeted-capture sequencing using RNA baits designed for 67 known or putative driver genes in myeloid neoplasms and 1,674 single nucleotide polymorphisms, which enabled detection of both mutations and copy number alterations on the same platform. In 9 of the 48 patients, pre- and post-therapy samples were further analyzed by whole exome sequencing (WES). Results: Average number of driver mutations before 5-aza was 2.8 per patient and 107 (90%) patients had multiple mutations. Most frequently mutated were TP53 (27%), followed by RUNX1, TET2, DNMT3A, and ASXL1. Reflecting high-risk disease subtypes of the subjects, splicing factor mutations were relatively rare (29 %) in the current cohort. Chromosomal abnormalities were identified in 65 (55%) patients, where 7q- and /or 5q- were the most frequent. Among 48 patients with serially collected samples, 46 had one or more mutations, enabling an evaluation of clone dynamics. In total 163 and 146 mutations were detected before and after treatment, respectively. About two thirds (110/163) of the mutations before 5-aza remained detectable after treatment. By contrast, the remaining one third showed a dynamic clonal behavior; 36 mutations in 22 cases were newly acquired, whereas 53 in 28 cases disappeared. Among those newly acquired, most frequently observed were mutations in STAG2 and EP300 (n = 3), of which STAG2 (7 cases) also represented the most frequent targets of disappeared mutations after treatment. In WES in 9 patients, a total of 112 mutations were identified either before or after 5-aza treatment with a mean of 10.4 or 8.9 mutations per sample, respectively. Among these, 63 were found at both pre- and post-therapy samples, whereas 17 and 32 mutations were newly acquired or disappeared during treatment, Given that only 4 newly acquired and 8 lost mutations had been detected by targeted-capture sequencing, respectively, WES enabled more sensitive detection of alternation of clones during 5-aza treatment, which were demonstrated in 8 (89%) subjects, rather than 5 (56%) in targeted-capture sequencing. Clinical outcomes have been reported for 22 patients as of the time of abstract submission; 5 achieved complete remission (CR), 9 stable disease (SD), and 5 progressive disease (PD). Alteration in clone size was frequently associated with clinical response. The size of dominant clones significantly decreased in 4 of 5 cases with CR, whereas stable or increased in 12 of 14 patients with SD or PD. In patients with SD or PD, acquisition of new mutations was common (10/14) during 5-aza treatment and potentially implicated in the resistance to 5-aza-treatment. Of interest, newly acquired mutations were also found in 2 CR samples, albeit at low allele frequency, even though the clone size of dominant clones was substantially reduced, suggesting the evolution of alternative MDS subclones or expansion of preexisting non-leukemic hematopoietic clone. Although CR was achieved in 3 of 6 patients with TP53 mutations, the TP53-mutationsdid not totally disappeared but were still detectable in CR samples in 2 cases, suggesting that TP53 mutated clones have not been completely eradicated by 5-aza treatment. Conclusion: Our study successfully depicted the structure of clones and their dynamics in high-risk MDS on 5-aza treatment. Alteration in the size of the dominant clones was frequently associated with a clinical response. Clonal evolution was common even in patients who achieved CR. Tracking the mutations in MDS patients during 5-aza treatment provides the opportunity to detect clones resistant to 5-aza and might be used to guide 5-aza therapy. Disclosures Kataoka: Kyowa Hakko Kirin: Honoraria; Boehringer Ingelheim: Honoraria; Yakult: Honoraria. Kiyoi:Celgene Corporation: Consultancy; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Chugai Pharmaceutical Co. LTD.: Research Funding. Naoe:Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene K.K.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding. Makishima:The Yasuda Medical Foundation: Research Funding. Ogawa:Sumitomo Dainippon Pharma: Research Funding; Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding.

scholarly journals Clonal evolution in myelodysplastic syndromes

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Pedro da Silva-Coelho ◽  
Leonie I. Kroeze ◽  
Kenichi Yoshida ◽  
Theresia N. Koorenhof-Scheele ◽  
Ruth Knops ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Clonal Evolution

scholarly journals Stem Cells in the Myelodysplastic Syndromes

2021 ◽  
Vol 2 ◽  
Author(s):  
Di Zhan ◽  
Christopher Y. Park
Keyword(s):  
Stem Cells ◽  
Myelodysplastic Syndromes ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Surface Proteins ◽  
Epigenetic Alterations ◽  
Hematopoietic Stem ◽  
Innate Immune Signaling ◽  
Novel Therapeutic Strategies

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

GATA2 Mutations In Pediatric Myelodysplastic Syndromes and Bone Marrow Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1520-1520 ◽  
Author(s):  
Inga Hofmann ◽  
Daniel Kierstead ◽  
Jennie Krasker ◽  
Dean Campagna ◽  
Klaus Schmitz-Abe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Sanger Sequencing ◽  
Pediatric Patients ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Family Members ◽  
Genetic Alterations ◽  
Cell Transplant ◽  
Monosomy 7

Abstract Introduction Inherited bone marrow failure syndromes (IBMFS), idiopathic aplastic anemia (AA), and myelodysplastic syndromes (MDS) represent a spectrum of bone marrow failure (BMF) conditions for which the underlying genetics and pathophysiology is still poorly understood. Heterozygous germline mutations in GATA2 have recently been described in three distinct conditions that include familial MDS/AML, Emberger syndrome and MonoMac syndrome, each of which exhibits great clinical heterogeneity. The Pediatric MDS and BMF Registry was established in 2010 to carefully characterize clinical and histopathologic phenotypes and investigate the molecular basis for these disorders. To date 158 eligible patients/probands and 28 family members have been enrolled. The goal of this study was to determine the prevalence of GATA2 mutations in pediatric patients with MDS and BMF and characterize their clinical and histopathologic phenotypes. Materials and Methods Sanger sequencing of GATA2 was initially performed on 3 families with a history of familial MDS and 103 patients with sporadic appearing primary MDS, AA or an unclassified BMF enrolled in the Pediatric MDS and BMF Registry. Family members were assessed in patients with pathogenic mutation to determine if the disease was inherited or sporadic. Mutations were confirmed in somatic and germline tissue wherever possible. IBMFS were ruled out by molecular testing. Rigorous phenotype analysis included clinical and laboratory data, and standardized centralized pathology review. Whole exome sequencing (WES) was performed on a subset of patients to evaluate additional cooperating mutations and possible secondary somatic events and clonal evolution. Possible candidate genes were verified by Sanger sequencing. Results We identified pathogenic GATA2 mutations in a total of 16 individuals, including 12 patients (7 familial MDS cases and 5 sporadic MDS/BMF cases) and 4 first-degree relatives from 5 kindreds. Most mutations clustered in zinc finger 2. Previously identified mutations such as N371K and R396Q as well as novel point and frame shift mutations were identified. The median age at diagnosis was 15 years. There was strong male predominance (n=11). The clinico-pathologic diagnoses were RAEB/AML (n=4), refractory cytopenia of childhood (n=6) and MonoMac/other (n=6). Two out of the four families presented with features of Emberger syndrome. Two individuals presented with characteristic features of MonoMac Syndrome, of which one also showed bone marrow failure and pulmonary fibrosis suggestive of telomere disease. Very short telomeres (below the first percentile) were detected in all lymphocyte subsets consistent with dyskeratosis congenita (DC). However, genetic analysis did not reveal any of the known DC associated genes. Other associated pathology included severe gastrointestinal bleeding (n=2), severe polyneuropathy (n=2) and other cancers (n=1). A morphologically distinctive megakaryocytic dysplasia was a characteristic finding on histopathology. Monosomy 7 was the most common acquired cytogenetic abnormalities (n=6). Given this association we identified several additional individuals with MDS and monosomy 7 from our pathology archives and identified 2 additional patients with pathogenic GATA2 mutations. Secondary somatic mutations identified by WES included ASXL1. Thirteen out of the 14 pediatric patients with GATA2 mutations underwent hematopoietic stem cell transplant (HSCT). Ten out of these 13 patients are alive. Conclusion GATA2 mutations occur at a higher frequency than previously anticipated in pediatric MDS, and BMF, often occur sporadically and are associated with monosomy 7. While the clinical presentation is heterogeneous, the histopathologic features are often unique. Somatic genetic alterations likely play a role in clonal evolution. Given its significant implications for treatment decisions and donor selection GATA2 mutation screening should be performed on all patients with MDS, AA, and BMF disorders excluding classical IBMFS, and potential related donors. Disclosures: No relevant conflicts of interest to declare.

Clonal Evolution Underlying the Progression from Myelodysplastic Syndromes to Ph-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5514-5514
Author(s):  
Masataka Taguchi ◽  
Tomoko Kohno ◽  
Hiroyuki Mishima ◽  
Hiroaki Taniguchi ◽  
Takeharu Kato ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Intron 1

Abstract Introduction: Myelodysplastic syndromes (MDS) are considered as a "stem cell disorders", in which hematopoietic stem cells and lineage-committed progenitor cells acquire genetic and epigenetic alterations and provide aberrant, clonal hematopoiesis, sometimes resulted in the progression to acute myeloid leukemia (Elias HK et al, Oncogene 2014). We previously reported a rare case of which the patient developed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) 2.5 years after being diagnosed with MDS (Kohno T et al, Br J Haematol 1996). p190 BCR-ABL1 mRNA was detected in the Ph+ALL cells. Metaphase cytogenetics showed the karyotypes: 46, XY, 20q- in MDS phase and 46, XY, t(9;22)(q34;q11), 20q- in ALL phase, indicating that MDS and Ph+ALL in this patient were of the same clonal origin. To uncover the detail of the clonal evolution, we analyzed bone marrow samples of MDS and Ph+ALL in this patient by targeted massively parallel sequencing with a panel of 154 genes including known driver genes of hematologic malignancies. Methods: Genomic DNAs (gDNAs) were extracted from the bone marrow mononuclear cells of MDS and Ph+ALL in this patient. Targeted sequencing was performed on the Illumina HiSeq2500 platform. Single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were called using HaplotypeCaller of Genome Analysis Toolkit (GATK) version 3.4-46. We also attempted to detect the breakpoint of BCR-ABL1 translocation from the targeted sequencing data using the computational method, BreaKmer (Abo RP et al, Nucleic Acids Research 2015). The candidates of the mutations and structural variations were validated by amplicon-based deep sequencing and Sanger sequencing. Copy number variations were analyzed using Affymetrix CytoScan HD Array. Results: The mutations in ASXL1 and U2AF1 genes were identified in the MDS sample with variant allele frequencies (VAFs) of about 45%. At the progression of Ph+ALL, the mutations in SETBP1, SMC1A, and SLC5A8 genes were newly acquired while the ASXL1 and U2AF1 mutations were also identified with the same level of VAFs (about 50%) as the other mutations. VAFs of all of the mutations were decreased to about 20% after the chemotherapy for Ph+ALL, and then increased to about 40% at the recurrence of the disease. Furthermore, we identified the breakpoint of BCR-ABL1 translocation at intron 1 of ABL1 genes and intron 1 of BCR genes, that is the well-known cluster region, m-bcr, only among the samples of Ph+ALL. Copy number analysis confirmed that both MDS and Ph+ALL samples harbored the deletion of chromosome 20q. And the deletion of IKZF1 gene, which is frequently identified in Ph+ALL cases (Mullighan CG et al, Nature 2008), was not identified during the progression from MDS to Ph+ALL. These results demonstrated that the MDS clone harboring 20q- and ASXL1 and U2AF1 mutations acquired the mutations in SETBP1, SMC1A, and SLC5A8 genes and the p190 BCR-ABL1, resulted in the development of Ph+ALL in this patient. Conclusion: The alterations of SETBP1, SMC1A, and SLC5A8 genes are usually reported in myeloid malignancies (Makishima H et al, Nat Genet 2013, Kon A et al, Nat Genet 2013, Whitman SP et al, Blood 2008). Previous study in transgenic mouse demonstrated the distinct role of p190 BCR-ABL1 in the development of an ALL (Voncken JW et al, Blood 1995). Recapitulating this scenario, p190 BCR-ABL1 may play a critical role in the development of Ph+ALL from the MDS stem cells in this patient. This study may provide a new insight into the stem cell origin of MDS and the role of p190 BCR-ABL1 in the development of Ph+ALL. Disclosures No relevant conflicts of interest to declare.

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