Myeloid malignancies with isolated 7q deletion can be further characterized by their accompanying molecular mutations

2019 ◽  
Vol 58 (10) ◽  
pp. 698-704
Author(s):  
Luise Hartmann ◽  
Claudia Haferlach ◽  
Manja Meggendorfer ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Myeloid Malignancies ◽  
7Q Deletion

Myeloid Malignancies with Isolated 7q Deletion Can be Further Characterized By Their Accompanying Molecular Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3811-3811
Author(s):  
Claudia Haferlach ◽  
Annette Fasan ◽  
Manja Meggendorfer ◽  
Melanie Zenger ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Array Cgh ◽  
De Novo ◽  
Jak2 V617f ◽  
Terminal Deletion ◽  
Employment Equity ◽  
Myeloid Malignancies ◽  
Additional Chromosome ◽  
Equity Ownership ◽  
De Novo Aml ◽  
7Q Deletion

Abstract Background: 7q deletions (del(7q)) are recurrent cytogenetic abnormalities. They occur either as the sole abnormality or accompanied by additional chromosome aberrations in AML, MDS, MDS/MPN and MPN. Cases with del(7q) as the sole abnormality are rare and poorly characterized. Aim: In patients with myeloid malignancies and del(7q) as the sole abnormality we determined 1. Type and size of the del(7q) 2. Spectrum of accompanying molecular mutations and their impact on the phenotype. Patients and Methods: 81 cases with myeloid malignancies and del(7q) as the sole abnormality were included in this study. Of these 38 had AML (27 de novo, 7 secondary, 4 therapy-related), 17 MDS (14 de novo, 3 therapy-related), 10 MDS/MPN (9 CMML, 1 MDS/MPN unclassifiable) and 16 MPN. The median age was 72 years (range: 29-89 years). All cases were investigated by array CGH (Agilent, Waldbronn, Germany) and for mutations in ASXL1, CALR, CBL, DNMT3A, ETV6, EZH2, JAK2, KRAS, MPL, NPM1, NRAS, RUNX1, SF3B1, SRSF2, TET2, and TP53. Results: Array CGH revealed an interstitial del(7q) in 67 cases, while 14 cases showed terminal del(7q). Further characterization of these deletions using 24 color FISH revealed unbalanced translocations in 10 of the 14 cases with terminal deletion. Partner chromosomes were X, 8, 9, 12, 13, 17 (n=2), 19 (n=2), and 22. The breakpoints on chromosome 7 were diverse ranging from 7q11 to 7q32. In two cases the breakpoint was within the CDK6 gene. In two cases with terminal del(7q) the complete loss of 7q was due to an idic(7)(q11.21). In the remaining two cases the terminal deletion could not be further resolved. In the 67 cases with interstitial del(7q) the size of the del(7q) varied between 1.8 and 158.9 Mb (median: 52.6 Mb). No commonly deleted region could be identified for all cases. However, in 57 cases the deleted region encompassed genomic position 101,912.442 (7q22.1) to 119,608.824 (7q31.31) including 111 genes. The size of the 7q deletion was smaller in cases with interstitial deletion as compared to terminal deletion (57.7 MB vs 70.9 MB, p=0.04) and in MPN as compared to all other entities (48.7 MB vs 62.8 MB, p<0.001). The mutation analyses revealed mutations in TET2 37% (25/67), ASXL1 35% (27/78), RUNX1 26% (18/69), DNMT3A 21% (14/68), SRSF2 18% (13/73), JAK2 V617F 14% (11/79), CBL 9% (7/75), NRAS 9% (7/77), MLL -PTD 5% (4/80), KRAS 5% (3/66), EZH2 4% (3/72), TP53 4% (3/74), SF3B1 4% (3/75), ETV6 3% (2/73), NPM1 3% (2/77), CALR 1% (1/77), MPL 1% (1/76). ASXL1 and TET2 were frequently co-mutated as 56% of ASXL1 mutated cases also harbored a TET2 mutation (p=0.02). 39 cases were analysed for all 16 molecular mutations. The majority of patients (n=27, 69%) had more than one mutation (range: 2-4), 9 patients (23%) had one mutation and in 3 patients (8%) no mutation was detected. The number of mutations per patient was lower in patients <70 years as compared to patients ≥70 years (0, 1,2,3,4 mutations detected in: 23%, 15%, 15%, 46%, and 0% vs 0%, 27%, 27%, 31%, and 15%, p=0.05). CBL mutations were most frequent in CMML (44%) but rare in all other subtypes (5%, p=0.003), while RUNX1 mutations were most frequent in AML (43% vs 9%; p=0.002) and JAK2 V617F mutations most frequent in MPN (50% vs 5%, p<0.001). DNMT3A mutations and MLL -PTD were significantly more frequent in de novo AML than in all other entities (43% vs 11%, p=0.007; 15% vs 0%, p=0.009), while no significant differences in frequency were observed between the different entities for any of the other mutations or the number of mutations per case. In CMML CBL mutations were associated with del(7q) (44%) as CBL mutations were present in only 17% of non del(7q) CMML (n=101, p=0.07). The frequency of RUNX1 mutations was significantly higher in AML with del(7q) as the sole abnormality (43%) as compared to all other AML (n=2273, 21%; p=0.001). Median overall survival (OS) for the total cohort was 25 months and did not differ significantly between AML, MDS, MDS/MPN and MPN (26, 27, not reached, 15 months, respectively). Conclusions: 1. Sizes and localisations of the del(7q) largely overlapped between AML, MDS, MDS/MPN and MPN. 2. 92% of all patients with 7q deletion harbored at least 1 molecular mutation. 3. TET2 and ASXL1 were the most frequently mutated genes and were present at comparable frequencies in all subtypes. 4. AML with del(7q) is closely associated with RUNX1 mutations while CMML with del(7q) frequently harbored CBL mutations suggesting a cooperative leukemogenic potential in these entities. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Fasan:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Zenger:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Targeted Detection of Copy Number Variants Using a Myeloid Malignancy Next Generation Sequencing Mutation Panel Allows Comprehensive Genetic Analysis Using a Single Testing Method

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2887-2887 ◽  
Author(s):  
Wei Shen ◽  
Philippe Szankasi ◽  
Maria Sederberg ◽  
Jonathan Schumacher ◽  
Kimberly Frizzell ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Microarray Analysis ◽  
Copy Number ◽  
Trisomy 8 ◽  
Genetic Profiling ◽  
Myeloid Malignancies ◽  
Snp Microarray ◽  
7Q Deletion ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Introduction Myeloid malignancies are clonal disorders of hematopoietic stem and progenitor cells that include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) myelodysplastic/myeloproliferative (MDS/MPN) overlap neoplasms, and acute myeloid leukemia (AML). Next generation sequencing (NGS) studies have identified a number of recurrently mutated genes that have diagnostic and/or prognostic significance in these disorders. Chromosomal copy number variations (CNVs) including deletions at 5q, 7q, 12p and 17p as well as trisomy 8, are another major type of recurrent genetic alteration with clinical significance in myeloid malignancies. Detection of CNVs has traditionally required specialized testing methods such as cytogenetics/FISH and/or array-based platforms. Thus, comprehensive genetic profiling of myeloid malignancies requires multiple testing strategies at high cost. In an effort to provide more efficient genetic profiling of these disorders, we designed and tested an algorithm to evaluate for CNVs using sequence coverage data derived from a NGS-based 53-gene myeloid mutation panel with the goal of obtaining information on both mutations and CNVs from a single test. Methods The sample cohort included 73 MDS patients, 36 patients with MDS/MPN neoplasms, 70 MPN patients, and 91 AML patients (n=270 total cases). Genomic DNA was extracted from bone marrow or peripheral blood, and enriched for regions of interest by solution capture (SureSelect, Agilent), then sequenced on the Illumina MiSeq, HiSeq 2000 or NextSeq NGS platforms. Gene variants were identified using the software programs FreeBayes, for single nucleotide variants and small insertions/deletions, and Pindel for larger insertions/deletions. To detect CNVs in the targeted regions, the read coverage data was normalized to a Log2 ratio which was generated by comparing the normalized sample coverage to that obtained from a pool of normal controls. CNVs were detected using a circular binary segmentation algorithm. In a subset of cases (n=43) CNVs detected using NGS data were validated by comparing to the results obtained by SNP microarray (CytoScan HD Array, Affymetrix) testing, the current gold standard, and analyzed by CHAS 2.0 (Affymetrix) and Nexus 7.5 (Biodiscovery). KMT2A (MLL) partial tandem duplications detected by NGS analysis were confirmed by quantitative PCR. Comparisons of proportions were performed by Fisher's exact test. Results In the entire cohort of 270 cases, we detected pathogenic mutations in 208 cases (77%). ASXL1 (n=64), SRSF2 (n=40), TET2 (n=39) and DNMT3A (n=37) were among the most frequently mutated genes as has previously been shown. For targeted CNV analysis, seven cases were excluded due to inadequate normalization of the read coverages. In the validation set of 43 cases, all of the targeted CNVs detected by NGS were confirmed by SNP microarray analysis (Figure 1A). Overall, we detected targeted CNVs in 68 cases (25.8%; AML n=32, MDS n=16, MDS/MPN n=9, MPN n=11). The most frequent CNVs were 7q deletion of a region including the genes LUC7L1 and EZH2 (n=21), TP53 deletion (n=9), ETV6 deletion (n=8), gain of RAD21 (possible trisomy 8) (n=8), and 5q deletion of a region including the genes NSD1 and NPM1 (n=4). In addition, we were able to detect exon-level duplications, the so-called KMT2A partial tandem duplication (also known as MLL -PTD), in 9 cases (Figure 1B). In the 63 cases that were negative by mutation analysis (MDS n=26, AML n=17, MDS/MPN n=5, MPN n=15), targeted CNVs including 7q deletion were observed in 4 cases (6%) (MDS n=3, AML n=1). In addition, targeted CNV analysis detected TP53 deletion in 3 TP53 -non-mutated cases and in 6 TP53 -mutated cases, and TET2 deletion in 2 TET2 -non-mutated cases and in 2 TET2 mutated cases. To investigate the association among gene mutations and targeted CNVs, we found that ETV6 deletion was strongly associated with TP53 alterations (both mutation and gene deletion; p<0.001) and 7q deletion was associated with mutations in TP53, KRAS and IDH1 (p= 0.000073, 0.009, 0.026, respectively). Conclusion Our results demonstrated the feasibility of using the same NGS data to detect both somatic mutations and targeted CNVs with enhanced efficiency and potentially lower costs compared to classical methods. Figure 1. Examples of targeted CNVs detected by NGS and comparison to SNP microarray analysis. Figure 1. Examples of targeted CNVs detected by NGS and comparison to SNP microarray analysis. Disclosures South: Affymetrix: Consultancy, Honoraria; ARUP Laboratories: Employment; Lineagen Corporation: Consultancy; Illumina: Consultancy, Honoraria.

R-2-Hydroxyglutarate Induces RIPK1-Dependent Necroptosis via Inhibition of KDM2B in Myeloid Malignancies

2020 ◽  
Author(s):  
Shuanghong Zhu ◽  
Chen Mei ◽  
Lingxu Jiang ◽  
Wenli Yang ◽  
Yingwan Luo ◽  
...  
Keyword(s):  
Myeloid Malignancies

scholarly journals The importance of evaluating specific myeloid malignancies in epidemiological studies of environmental carcinogens

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
K. A. Mundt ◽  
L. D. Dell ◽  
P. Boffetta ◽  
E. M. Beckett ◽  
H. N. Lynch ◽  
...  
Keyword(s):  
Tobacco Smoking ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Epidemiological Studies ◽  
Sufficient Evidence ◽  
International Agency ◽  
Environmental Carcinogens ◽  
Epidemiological Evidence ◽  
Myeloid Malignancies ◽  
Chemical Agents

Abstract Introduction Although myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN) – including chronic myeloid leukemia (CML) – and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are largely clinically distinct myeloid malignancies, epidemiological studies rarely examine them separately and often combine them with lymphoid malignancies, limiting possible etiological interpretations for specific myeloid malignancies. Methods We systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes “myeloid malignancies.” Literature searches of IARC Monographs and PubMed identified 85 studies that we critically assessed, and for appropriate subsets, summarized results using meta-analysis. Results Only two epidemiological studies on 1,3-butadiene were identified, but reported findings were inadequate to evaluate specific myeloid malignancies. Studies on formaldehyde reported results for AML and CML – and not for MDS or MPN – but reported no increased risks. For benzene, several specific myeloid malignancies were evaluated, with consistent associations reported with AML and MDS and mixed results for CML. Studies of tobacco smoking examined all major myeloid malignancies, demonstrating consistent relationships with AML, MDS and MPN, but not with CML. Conclusions Surprisingly few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. This exercise illustrates that even for agents classified as having sufficient evidence of causing “myeloid malignancies,” the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent. Future epidemiological studies should report findings for the specific myeloid malignancies, as combining them post hoc – where appropriate – always remains possible, whereas disaggregation may not. Furthermore, combining results across possibly discrete diseases reduces the chances of identifying important malignancy-specific causal associations.

scholarly journals Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish

Leukemia ◽  
2021 ◽  
Author(s):  
Xiao Fang ◽  
Song’en Xu ◽  
Yiyue Zhang ◽  
Jin Xu ◽  
Zhibin Huang ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Nonsense Mutations ◽  
Myeloid Malignancies ◽  
A Subunit ◽  
Neutrophil Differentiation ◽  
Polycomb Repressive Complex 1 ◽  
Myelomonocytic Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

AbstractASXL1 is one of the most frequently mutated genes in malignant myeloid diseases. In patients with myeloid malignancies, ASXL1 mutations are usually heterozygous frameshift or nonsense mutations leading to C-terminal truncation. Current disease models have predominantly total loss of ASXL1 or overexpressed C-terminal truncations. These models cannot fully recapitulate leukemogenesis and disease progression. We generated an endogenous C-terminal-truncated Asxl1 mutant in zebrafish that mimics human myeloid malignancies. At the embryonic stage, neutrophil differentiation was explicitly blocked. At 6 months, mutants initially exhibited a myelodysplastic syndrome-like phenotype with neutrophilic dysplasia. At 1 year, about 13% of mutants further acquired the phenotype of monocytosis, which mimics chronic myelomonocytic leukemia, or increased progenitors, which mimics acute myeloid leukemia. These features are comparable to myeloid malignancy progression in humans. Furthermore, transcriptome analysis, inhibitor treatment, and rescue assays indicated that asxl1-induced neutrophilic dysplasia was associated with reduced expression of bmi1a, a subunit of polycomb repressive complex 1 and a reported myeloid leukemia-associated gene. Our model demonstrated that neutrophilic dysplasia caused by asxl1 mutation is a foundation for the progression of myeloid malignancies, and illustrated a possible effect of the Asxl1-Bmi1a axis on regulating neutrophil development.

scholarly journals Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

2021 ◽  
Vol 10 (13) ◽  
pp. 2788
Author(s):  
Suncica Kapor ◽  
Juan F. Santibanez
Keyword(s):  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Chemotherapy Resistance ◽  
Leukemia Cell ◽  
Suppressor Cells ◽  
Leukemic Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Hematopoietic Stem ◽  
Myeloid Malignancies ◽  
Adaptive Immune Systems

Myeloid malignancies arise from an altered hematopoietic stem cell and mainly comprise acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic leukemic cells may influence the growth and differentiation of other hematopoietic cell lineages in peripheral blood and bone marrow. Myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs) display immunoregulatory properties by controlling the innate and adaptive immune systems that may induce a tolerant and supportive microenvironment for neoplasm development. This review analyzes the main features of MDSCs and MSCs in myeloid malignancies. The number of MDSCs is elevated in myeloid malignancies exhibiting high immunosuppressive capacities, whereas MSCs, in addition to their immunosuppression contribution, regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance. Moreover, MSCs may promote MDSC expansion, which may mutually contribute to the creation of an immuno-tolerant neoplasm microenvironment. Understanding the implication of MDSCs and MSCs in myeloid malignancies may favor their potential use in immunotherapeutic strategies.

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