scholarly journals Gene mutation spectrum of patients with myelodysplastic syndrome and progression to acute myeloid leukemia

2021 ◽  
pp. IJH34
Author(s):  
Ming Liu ◽  
Fang Wang ◽  
Yang Zhang ◽  
Xue Chen ◽  
Panxiang Cao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Sequencing Technology ◽  
Transcription Factor Genes ◽  
Spectrum Of Patients ◽  
Acute Myeloid

Aim: This study aimed to investigate the regularity of gene mutations in patients with myelodysplastic syndrome (MDS) and in those that progressed to acute myeloid leukemia (MDS/AML). Patients & methods: High-throughput sequencing technology was used to detect gene mutations in 99 newly diagnosed patients with MDS or MDS/AML. Results: Gene mutations were detected in 88 patients. The mutation incidence in the MDS/AML group was significantly higher than that in the MDS group. Statistically significant differences were observed between the MDS with refractory anemia (MDS-RA) and MDS-RA with excess blasts groups and between the MDS/AML and MDS-RA groups. Conclusion: Our data demonstrate that there is a cumulative accumulation of gene mutations, especially in transcription factor genes, during disease progression in MDS and MDS/AML.

scholarly journals HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Zhengchang He ◽  
Siyu Zhang ◽  
Dan Ma ◽  
Qin Fang ◽  
Liping Yang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Tumor Cells ◽  
High Throughput ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Ezh2 Expression ◽  
Very High ◽  
Acute Myeloid

Abstract Background Myelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy (decitabine) does not effectively inhibit tumor cells. Enhancer of zeste homologue 2 (EZH2) and Heme oxygenase-1 (HO-1) are two key factors in patients resistance and deterioration. Methods In total, 58 MDS patients were divided into four groups. We analyzed the difference in HO-1 and EZH2 expression among the groups by real-time PCR. After treatment with Hemin or Znpp IX, flow cytometry was used to detect apoptosis and assess the cell cycle distribution of tumor cells. Following injection of mice with very high-risk MDS cells, spleen and bone marrow samples were studied by immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining. MDS cells overexpressing EZH2 and HO-1 were analyzed by high-throughput sequencing. The effect of HO-1 on the pRB-E2F pathway was analyzed by Western blotting. The effects of decitabine on P15INK4B and TP53 in MDS cells after inhibiting HO-1 were detected by Western blotting. Results Real-time PCR results showed that EZH2 and HO-1 expression levels were higher in MDS patients than in normal donors. The levels of HO-1 and EZH2 were simultaneously increased in the high-risk and very high-risk groups. Linear correlation analysis and laser scanning confocal microscopy results indicated that EZH2 was related to HO-1. MDS cells that highly expressed EZH2 and HO-1 infiltrated the tissues of experimental mice. IHC results indicated that these phenomena were related to the pRB-E2F pathway. High-throughput sequencing indicated that the progression of MDS to AML was related to EZH2. Using the E2F inhibitor HLM006474 and the EZH2 inhibitor JQEZ5, we showed that HO-1 could regulate EZH2 expression. HO-1 could stimulate the transcription and activation of EZH2 through the pRB-E2F pathway in MDS patients during chemotherapy, which reduced TP53 and P15INK4B expression. Conclusions EZH2 was associated with HO-1 in high-risk and very high-risk MDS patients. HO-1 could influence MDS resistance and progression to AML.

Sequential Molecular Characterization Based Delineation of Potential Driver Aberrations in ACUTE Myeloid Leukemia Following Myelodysplastic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4123-4123
Author(s):  
Frank G. Rücker ◽  
Sibylle Cocciardi ◽  
Anna Dolnik ◽  
Tamara J. Blätte ◽  
Ulrike Wüst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Gene Mutations ◽  
Advisory Committees ◽  
Multistep Process ◽  
Genomic Aberrations ◽  
Acute Myeloid

Abstract Background: Myelodysplastic syndrome (MDS) patients exhibit an increased risk of progression towards secondary acute myeloid leukemia (sAML) with poor prognosis. The mechanisms underlying transformation from MDS to sAML are largely unknown. Aims: To identify genetic lesions associated with transformation in AML [copy number alterations (CNA), chromothripsis, uniparental disomies (UPD), and gene mutations], we performed genome-wide SNP array 6.0 profiling and mutational screening of 9 AML associated genes (RUNX1, TP53, NPM1, NF1, FLT3, ASXL1, DNMT3A, IDH1 and IDH2) in 42 paired MDS/sAML samples including 5 relapsed AML samples (rAML) [WHO MDS categories: RA (n=5), RCMD (n=12), RAEB-I (n=10), RAEB-II (n=8), 5q- (n=1), CMML-1 (n=1), CMML-2 (n=1), unclassifiable (n=4)]. In addition, whole exome sequencing (WES) was performed in 10 selected cases. Results: In total, 26 (62%) patients acquired genomic aberrations [CNAs and/or UPDs] at diagnosis of sAML as compared to the corresponding MDS sample. Most frequent numerical aberrations were trisomy 8 (n=7) and monosomy 7 (n=4); recurrent submicroscopic losses were identified at 17q11.2 (n=6, encompassing NF1), 17p13 (n=2, TP53), 12p13 (n=2, ETV6), and 21q22.12 (n=2, RUNX1); biallelic 17q11.2 and 21q22.12 losses were detected in one sAML each. Of note, all chromosome 5 alterations (n=11) were already present in MDS. Six (14%) cases acquired UPDs affecting the regions 1p, 11q, 13q, 20q, and 21q (n=2). Paired sequencing of candidate genes in 1p, 13q, and 21q delineated UPD related homozygous mutation patterns for pre-existing heterozygous NRAS, FLT3 -ITD, and RUNX1 mutations in sAML. Acquired AML associated gene mutations were identified in 11 (26%) patients with RUNX1 mutations being the most frequent. Sequential sequencing revealed mutation incidences in MDS and sAML as follows: RUNX1, 17% and 26%; TP53, 19% and 21%; ASXL1, 14% and 17%; DNMT3A, 12% and 14%; NF1, 10% and 14%; NPM1, 7% each; FLT3, 2% and 5%; IDH2, 2% and 5%; and IDH1, 2% each, respectively. While in the NPM1 mutated sAML cases the mutation was already present in the MDS sample (RCMD, n=2; RAEB-I, n=1), all cases transformed quickly within 5 to 6 months into AML compared to NPM1 wildtype MDS patients with a median time to transformation of 14 months. Other variables predicting inferior transformation free survival were biallelic TP53 alteration (n=5; p=.006), chromothripsis (n=4; p=.03), and presence of >4 CNAs (n=10; p=.04). Additional analysis of 5 rAML samples displayed aberration patterns closely related to the sAML in 4 cases; only one rAML seems to be evolved from an ancestral pre-MDS clone. In selected cases with available material (n=10) WES identified an average of 3.5 additional mutations per sAML. These included not only mutations in genes known to be associated with transformation (like e.g. NRAS, RUNX1, ETV6,and FLT3) but also in potential novel driver genes such as e.g. AFF1, NSD1, and STAG2. In accordance, the mutational pattern was not only significantly enriched for genes known to be associated with AML, but also for genes located in commonly gained regions of tumor genomes. Summary/Conclusions: Over two thirds (71%) of MDS cases acquired additional genetic abnormalities during progression to sAML as detected by SNP profiling and conventional Sanger sequencing; WES suggests that in all cases additional mutations are acquired. The genetic spectrum of our cohort demonstrates a multistep process for leukemogenesis with mutations and genomic aberrations occurring over time. Deletion 5q and mutations in DNMT3A and ASXL1 seem to be early events usually already found in MDS, and UPDs and alterations of RUNX1 and NF1 rather late events acquired in sAML. Ongoing extensive molecular analyses will further unravel the genetic aberrations involved in this multistep process. Supported by: FP7 NGS-PTL project. LB and KD contributed equally. Disclosures Schlenk: Pfizer: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Arog: Honoraria, Research Funding.

Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1866-1868 ◽  
Author(s):  
Hesham M. Amin ◽  
Iman Jilani ◽  
Elihu H. Estey ◽  
Michael J. Keating ◽  
Amanda L. Dey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
B Lymphocytes ◽  
Myeloid Leukemia ◽  
Immune Modulation ◽  
Refractory Anemia ◽  
Healthy Controls ◽  
Microenvironmental Factors ◽  
Acute Myeloid

AbstractThe hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of MDS.

scholarly journals Cytogenetic study of 50 Brazilian patients with primary myelodysplastic syndrome

1997 ◽  
Vol 20 (1) ◽  
pp. 87-91 ◽  
Author(s):  
Teresa de Souza Fernandez ◽  
Maria Luiza M. Silva ◽  
Jamison M. de Souza ◽  
Daniel Tabak ◽  
Eliana Abdelhay
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Cytogenetic Study ◽  
Elevated Risk ◽  
Chronic Myelomonocytic Leukemia ◽  
Refractory Anemia ◽  
Ringed Sideroblasts ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

In this work we analyzed cytogenetically 50 patients with primary myelodysplastic syndrome from several hospitals of Rio de Janeiro, Brazil. The frequency of cytogenetic abnormalities was 32%. Patients with refractory anemia, or refractory anemia with ringed sideroblasts, presented normal karyotypes or single abnormalities such as del(5q) or -Y, while patients with refractory anemia with an excess of blasts, refractory anemia with an excess of blasts in transformation or chronic myelomonocytic leukemia showed complex karyotypes and single abnormalities involving chromosomes 7 or 8, which are related to a bad prognosis and an elevated risk of evolution to acute myeloid leukemia.

Genomic profile at diagnosis by targeted high throughput sequencing, and real-world clinical outcomes in patients diagnosed with acute myeloid leukemia at a tertiary care cancer center.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19515-e19515
Author(s):  
Vivek Sulekha Radhakrishnan ◽  
Arunima Bhaduri ◽  
Neeraj Arora ◽  
Reena Nair ◽  
Shreya Bhattacharya ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Throughput ◽  
Real World ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Tertiary Care ◽  
Gene Mutations ◽  
Risk Groups ◽  
Data Set ◽  
Acute Myeloid

e19515 Background: Acute Myeloid Leukemia (AML) is a highly heterogeneous disease. High throughput sequencing (HTS) has led to the discovery of a number of recurrently mutated genes in AML & has provided a detailed molecular landscape of the disease. This information is now extensively utilised & interpreted in AML. Methods: Retrospective analysis of 47 patients with newly diagnosed AML for those who had both cytogenetic and targeted HTS information at diagnosis, [median age: 44y (12-80y); 24 females] & treated at Tata Medical Center, India between 2013-2019. HTS was performed using Illumina Trusight myeloid panel and/or Thermo Fisher Scientific Oncomine Myeloid panel, and mutation data from the common 28 genes were used. Patients were stratified by European Leukemia Net (ELN) 2010 and 2017 guidelines. Standard of care clinical outcome data was available for all patients. Results: 45 of 47 patients had mutations. The most frequently mutated gene was FLT3 (n = 13, 28.9%), followed by NPM1 (n = 8, 17.8%), and others [ IDH1, IDH2, TET2, CEBPA, and NRAS; n = 7, 15.6%). ELN-2010 classified 6 patients as Favourable (12.8%), 10 as Intermediate-I (21.3%), 25 as Intermediate-II (53.2%) and 6 as Adverse (12.8%) risk groups. One patient migrated to the adverse group from Intermediate-II when ELN-2017 was applied. ELN 2017 re-classification: Favorable (n = 6, 12.8%), intermediate (n = 34, 72.3%), and adverse risk groups (n = 7, 14.9%). Co-occurrence of driver gene mutations was found in NPM1 and FLT3 (8.2%) frequently. Patients with mutations in epigenetic modifiers ( ASXL1, IDH1, IDH2, DNMT3A) had high Variant Allele Frequency (VAF, 40-50%) while those with signaling pathway gene mutations ( NRAS, KRAS) had low VAF (9-25%). At a median follow up of 3.25 years, median overall survival in the three risk groups (favorable, intermediate, adverse) were 11.25 mons, 7 mons and 8 mons respectively, and relapse rates were 16%, 29% and 42% respectively. Conclusions: Early experience from a middle-income real-world setting suggests feasibility of integration of HTS information in practise, as additional prognostic/ predictive information. The pattern of a high VAF in epigenetic modifier gene mutations, potentially as a result of early acquisition during clonal development, needs further evaluation. This data set has helped us initiate a prospective multimodal omics study at our institution.

Association of Gastrointestinal Stromal Tumor and Acute Myeloid Leukemia Preceded by Myelodysplastic Syndrome with Refractory Anemia

2009 ◽  
Vol 95 (2) ◽  
pp. 240-242 ◽  
Author(s):  
Mehmet Sonmez ◽  
Mehmet Arslan ◽  
Umit Cobanoglu ◽  
Halil Kavgaci ◽  
Hasan Mucahit Ozbas ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Gastrointestinal Stromal Tumor ◽  
Myeloid Leukemia ◽  
Stromal Tumor ◽  
Refractory Anemia ◽  
Acute Myeloid

Comparative Single Institute Analysis of Cord Blood Transplantation From Unrelated Donors with Unrelated Bone Marrow or Related Peripheral Blood Stem-Cell Transplants in Adult Patients with Acute Myeloid Leukemia / Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3382-3382
Author(s):  
Kazuhiro Masuoka ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
Hisashi Yamamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract Abstract 3382 Poster Board III-270 Recently, unrelated cord blood transplant (UCBT) has been widely applied to those who lack available related or unrelated donors. However, some results in those reports were conflicting, especially for transplantation-related mortality (TRM). The US study demonstrated a poor outcome for TRM in CBT recipients compared with human leukocyte antigen (HLA)–matched bone marrow transplant (BMT) recipients (NEJM. 2004; 351:2265). On the other hand, Takahashi et al showed excellent outcome (TRM 9% and disease free survival, DFS 70%) in CBT (Blood. 2007; 109:1322). Since there has been not much data available regarding this issue, we retrospectively extracted to adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS) and analyzed retrospectively the results of 245 recipients who underwent allogeneic stem cell transplantation (allo-SCT). We reviewed medical records of 290 patients with AML/MDS who had received allo-SCT from an unrelated donor between June 2000 and March 2009 at our institute, Tokyo, Japan. Since patients who had previous hematopoietic stem cell transplantations, active serious infection and performance status > 2, were excluded, 45 were subjected to the following analysis. Finally, the study includes 245 recipients of UCB (n = 140), UBM (n = 63), and related mobilized peripheral blood (RPB, n = 42) for de novo AML (n = 132), MDS overt AML (n = 79), refractory anemia (RA, n = 15), and refractory anemia with excess of blasts (RAEB, n = 19). Patient s median age for UCB, UBM, and RPB recipients were 59 (17 - 72), 55 (23 – 70), and 55 (22 – 67), respectively. UCB recipients had more serologically HLA-mismatched grafts (97% vs. 38% vs. 22%, P < .01), were conditioned more frequently with melphalan (75% vs. 27% vs. 20%, P < .01) and with total body irradiation (86% vs. 80% vs. 12%, P < .01 and used more tacrolimus (78% vs. 81% vs. 15%, P < .01) and less methotrexate (0% vs. 98% vs. 85%, P < .01) for graft-versus-host disease (GVHD) prophylaxis. Disease status consisted of standard (CR1 or CR2 of AML and RA, n = 62) and advanced groups(other status, n = 183). UCB recipients had significantly advanced status relative to UBM and RPB recipients (84% vs. 57% vs. 69%, P < .01) at the time of transplantation. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 787 days (119 – 2314), 1050 days (244 – 3059), and 1287 days (141 – 3004) for UCB, UBM, and RPB recipients, respectively. The incidence of grade II–IV acute GVHD among evaluable UCB recipients was lower than those of UBM and RPB recipients (32% vs. 54% vs. 59%, P < .01). Similarly, the incidences of chronic GVHD for evaluable UCB, UBM, and RPB recipients were 36%, 69%, and 66%, respectively (P < .01). The estimated overall survival (OS) and DFS rates at 5 years post-transplantation were 36% (95% confidence interval Åm95%CIÅn; 25 - 47%) and 35% (95%CI; 26 - 44%) for UCB, 55% (95%CI; 40 - 69%) and 51% (95%CI; 37 - 64%) for UBM, and 39% (95%CI; 22 - 55%) and 25% (95%CI; 8 - 41%) for RPB (OS, P < .01 and DFS, P < .01). In the standard group, OS and DFS rates were not significantly different in the three groups (OS, UCB 63% vs. UBM 70% vs. RPB 49%, P = .39 and DFS, UCB 63% vs. UBM 70% vs. RPB 39%, P = .10). Similarly, in the advanced group, there were not significantly difference in the three groups (OS, UCB 30% vs. UBM 41% vs. RPB 35%, P = .23 and DFS, UCB 29% vs. UBM 38% vs. RPB 24%, P = .27). Compared with UBM and RPB recipients, UCB recipients had delayed hematopoietic recovery at 60 day (UCB 85% vs. UBM 97% vs. RPB 100%, Hazard ratio ÅmHRÅn= 0.49; 95%CI: 0.40 0.59; P < .01). Five-year estimated TRM and relapse rate (RR) were not significantly different in the three groups (TRM, UCB 34% vs. UBM 29% vs. RPB 50%, P = .39 and RR, UCB 30% vs. UBM 20% vs. RPB 28%, P = .28). < Conclusion> In this analysis, there was no apparent difference in the risks of TRM and RR between the UCB and UBM/RPB recipient groups. OS and DFS in both groups were also comparable among standard and advanced groups. Finally, our clinical results suggest that UCBT could be as safe and effective a stem-cell source as UBMT or RPB transplant for adult AML/MDS patient. Disclosures: No relevant conflicts of interest to declare.

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