scholarly journals Novel Synthetic Lethal Targets for Myeloid Neoplasms with Loss of Chromosome 7

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3346-3346
Author(s):  
Minako Mori ◽  
Vera Adema ◽  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
Laila Terkawi ◽  
...  
Keyword(s):  
Copy Number ◽  
Bone Marrow Failure ◽  
Embryonic Lethality ◽  
Therapeutic Window ◽  
Molecular Profile ◽  
Synthetic Lethal ◽  
Tp53 Mutations ◽  
Ras Genes ◽  
Myeloid Neoplasms ◽  
Dna Repair Gene

Abstract Loss of chr7 (-7) and partial deletions of its long arm (del7q) are observed in 10% of de novo myeloid neoplasms (MNs), 50% of therapy related MDS, up to 60% of post aplastic anemia MNs and occur frequently as evolution of congenital bone marrow failure syndromes (e.g., GATA2 and SAMD9L deficiency, FA). LOH of one or more chr7 genes has been considered the culprit in the pathogenesis of -7/del7q MNs. In addition to the loss of protective alleles, deletion resulting in haploinsufficiency (HI) of tumor suppressor genes (TSGs) in CDRs might be also a cause of leukemogenic drive behind -7/del7q. To date, albeit many candidate genes have been associated with -7/del7q, the search for genes responsible for clinical phenotype has failed to identify causative -7/del7q TSGs and their putative loss would be difficult to target. Irrespective of the important goal of clarification of leukemogenic effects of -7/del7q, loss of genes in CDRs may create a vulnerability phenotype, which could be exploited with synthetic lethal approaches. Such strategies would rely on the higher resistance of diploid vs -7/del7q cells, thus allowing for a therapeutic window. Here, we studied the molecular profile of 8160 MN patients (del7q: 1.7%; -7: 6%). EZH2 mutations were enriched in -7/del7q compared to chr7 diploid cases (3.8 vs 1.2%, P<.0001) also by absolute numbers heterozygous mutations were more numerous. We also detected somatic CUX1 mutations (1.7 vs 0.9%), SAMD9/SAMD9L (0.3 vs 0.1%), and LUC7L2 (0.3 vs 0.1%) in -7/del7q vs diploid. In -7/del7 cases somatic alterations were detected in BRAF (n=7), POT1 (n=3), PCLO (n=5) and PSMC2 (n=1) while no mutations in CUL1 and KMT2C were found. We then investigated the presence of driver mutations located on other chromosomes in -7/del7q. Del7q/-7 cases showed a lower frequency of TET2 and SF3B1 mutations vs diploid cases. In isolated/+1 del7q/-7 cases, TP53 mutations were significantly less frequent, but were increased in -7/del7q with complex karyotype (P<.0001). Higher frequencies of RAS genes, RUNX1 and ETV6 hits were also found. Del7q and TP53 mutations were founder lesions (dominant) in 38% and 54% of -7/del7q, while -7 was dominant in 63% of -7 cases. TP53 was the only mutation significantly associated with further worsening the already poor prognosis of -7/del7q cases (HR=1.629 P< .01). Germline alterations were more common in -7/del7q as compared to diploid cases (13 vs 5% P< .0001) of which most were FA or DNA repair gene variants also in other genes including (e.g., SAMD9L, 7%, DDX41, 3.7%). Having defined the genotype of -7/del7q, we set to identify genes which could be possible targets for the therapy chiefly synthetic lethality. Criteria for selection included: consistent HI in most of the patients, genes not affected by hemizygous LOF mutations and embryonic lethality in knockout (KO) configuration. Expression data of -7/del7q (n=86), diploid cases (n=1066) and healthy controls (n=84; MLL and BEAT AML to increase precision) were analyzed. Our algorithm included selection of genes with mRNA expression inversely correlating with copy number (deletion copy number). Out of 694 genes on chr7, 147 genes were deleted in all patients and 101 genes had more inconsistent HI levels. In total 35 genes showed significant negative correlation with -7/del7q ploidyincluding ACTR3B,AGK,ATP06V0E2,CUL1,FASTK,GALNT11,GSTK1, IMPDH1, PLXNA4, SLC37A3, ZNF277, KMT2C, NUP205, TMEM209, ZC3HC1 and GIMAP1/2/4/6, a cluster ofnucleotide binding proteins. Following adjustment to ploidy, HI was found for EZH2 (76% cases), CUX1 (76%), KMT2C (70%), LUC7L2 (60%), and SAMD9/9L (32%/50%) but also even more consistently in SSBP1 (88%), PSMC2 (86%), CUL1, ZNF398, and RHEB (all 84%) and TNPO3 (82%). Among those genes homozygous KO of Ezh2 and Cul1 lead to embryonic lethality, Gimap family deletion reduces normal hematopoiesis, Samd9l +/-and Samd9l-/- mice develop MDS and die after 1.5yrs and Cux1 knockdown causes an MDS like phenotype. Existing inhibitors are available for CUL1 (MLN4924), CUX1 (BER modulating agents) and EZH2 (EPZ6438, GSK343), but the presence of homozygous mutations (UPD7q) argues that EZH2 inhibition is unlikely to be successful. In conclusion, we showed a comprehensive molecular topography of -7/del7q and identified novel HI genes which could be targeted by novel or repurposed drugs. Ongoing drug screens for identified targets performed in cells with -7/del7q will be presented at the meeting. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

scholarly journals Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1234
Author(s):  
Jérôme Raffenne ◽  
Fernando A. Martin ◽  
Rémy Nicolle ◽  
Marina Konta ◽  
Yuna Blum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Protein Identification ◽  
Molecular Profile ◽  
Global Methylation ◽  
Old Patients ◽  
Molecular Features ◽  
Age Related ◽  
Clinical Difference ◽  
Dna Repair Gene

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

scholarly journals The clinical impact of copy number variants in inherited bone marrow failure syndromes

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Nicolas Waespe ◽  
Santhosh Dhanraj ◽  
Manju Wahala ◽  
Elena Tsangaris ◽  
Tom Enbar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Copy Number Variants ◽  
Clinical Impact ◽  
Bone Marrow Failure Syndromes

scholarly journals Detection of Mutations in Inherited Bone Marrow Failure and Myelodysplastic Syndrome Genes Using Genomic Capture and Massively Parallel Sequencing in Clinical Diagnostics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1507-1507
Author(s):  
Siobán B. Keel ◽  
Tom Walsh ◽  
Colin Pritchard ◽  
Akiko Shimamura ◽  
Mary-Claire King ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Genetic Testing ◽  
Hematopoietic Stem Cell ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Copy Number Variants ◽  
Donor Selection ◽  
Hematopoietic Stem ◽  
Pathogenic Mutations

Abstract Accurate and timely diagnosis of inherited bone marrow failure (BMF) and myelodysplastic syndromes (MDS) ensures appropriate clinical management. The correct diagnosis allows appropriate monitoring for both hematopoietic (i.e. clonal evolution and progressive marrow failure) and extra-hematopoietic complications, informs the timing of hematopoietic stem cell transplant, donor selection and transplant regimen planning, and ensures appropriate genetic counseling of family members. Substantial phenotypic overlap among these disorders and the variable expressivity within syndromes complicate their diagnosis based purely on physical exam and standard laboratory testing and provide the rationale for comprehensive genetic diagnostic testing. We report here our initial one-year experience utilizing a targeted capture assay of known inherited BMF/MDS genes for clinical diagnostic purposes at the University of Washington. The assay sequences all exons and 20 base pairs of intronic sequence flanking each exon, as well as several regulatory and intronic regions of specific genes containing known pathogenic variants of 85 known inherited BMF/MDS genes (Zhang M. et al. Haematologica 2016). Between June 2015 and July 2016, 81 individual patients were referred for clinical testing (median age: 15 years-old, range: 0.6-76 years-old). For all samples evaluated, median coverage across the 383kb targeted region was 1887X. This depth of coverage enabled identification of all classes of mutations, including point mutations, small indels, copy number variants, and genomic rearrangements. Pathologic mutations in known inherited BMF/MDS genes were identified in 12 of 82 (14.6%) individuals (median age 13 years-old, range: 1.25-43 years-old) across a broad number of genes and of multiple classes including copy number variants (Table). Among the twelve patients with pathogenic mutations in inherited BMF/MDS genes, genetic testing was consistent with the prior clinical diagnoses of eight patients, including two Fanconi anemia patients subtyped as complementation group A, one of whom demonstrated reversion to wild-type resulting in mosaicism in the peripheral blood. Importantly, four patients carried no specific inherited BMF/MDS diagnosis prior to testing and were found to have pathogenic mutations in RPS10, RTEL1 and RUNX1 (ID 005, 008, 009, 010), suggesting additional diagnostic value to a multiplexed genetic approach in the clinical setting. Detailed clinical information was available for nine of the patients diagnosed with pathogenic mutations, two of whom have or will undergo a sibling or haploidentical hematopoietic stem cell transplantation (009 and 012, respectively) and thus genetic testing informed donor selection. To improve diagnostic accuracy, we are now updating the capture design to include newly discovered inherited BMF/MDS genes and intronic regions to optimize copy number variant detection. We are additionally pursuing CLIA-certified RNA analyses to characterize whether several variants bioinformatically predicted to affect splicing are functionally deleterious. Next-generation sequencing for mutations involved in hereditary marrow failure and MDS may also become increasingly important in the context of precision-medicine in which germline mutations are unexpectedly identified in somatic testing. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Genomic Landscape of Myeloid Neoplasms Evolved from AA/PNH

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
Bhumika J. Patel ◽  
Hassan Awada ◽  
Cassandra M Kerr ◽  
...  
Keyword(s):  
Immune Escape ◽  
De Novo ◽  
Mutational Analysis ◽  
Germ Line ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Class I ◽  
Molecular Characteristics ◽  
Cross Sectional ◽  
Tp53 Mutations

Up to 15% of AA patients (pts) treated conservatively with immunosuppression will evolve to myeloid neoplasia (MN), either MDS or AML, over a median time of 10 years regardless of response (0-18 years; n=238). The pathogenesis of MN secondary to AA is diverse and will often include antecedent clonal facilitating events that herald progression. Minor clones have been described in AA, some of which are not contributory to later evolution while other may result in subsequent progression. MDS evolution in inherited bone marrow failure (BMF) syndromes suggests that germ line (GL) alterations can be predisposing. In addition, progression to MN may reflect immune escape due to selection pressure e.g., through acquisition of HLA mutations. Here, we studied the molecular landscape of MN arising from AA, to better understand its pathogenesis and ultimately to develop measures of early detection, prevention, and therapeutic strategies. Among 350 pts diagnosed with AA and PNH, 38 (11%) developed a secondary MN (sMN). Median age at AA/PNH diagnosis was 61 years (15-76). Almost all of pts who underwent transformation (89%) received a 1st line treatment consisting of ATG+CsA in 85% of cases (ORR 59%; 21% CR and 38% PR) and 47% received more than one form of treatment, suggesting a lack/incomplete response or relapse. MDS was the most frequent diagnosis at evolution (77%), followed by AML (21%) and MPN (2%). Myeloid evolution was less common in pts with moderate AA (7% vs 14% in severe) or in the presence of a PNH clone (21% vs. 52% in non-progressors, p=.0003). First we investigated GL alterations classified as Tier1 (9/38 pts) and Tier2 (11/38) based on their pathophysiological impact. Tier1 variants included NF1, CBLC, SBDS (n=2), and SAMD9L and overall were more frequently detected in del(7q) pts (76%, p=.0001). Tier2 included FA variants (BRCA2, FANCI, FANCD2; n=3). Of note, in sMN Tier1 variants were detected in 24% vs. 8% in non-evolved cases (p=.008) and none had concomitant Tier1/Tier2 configuration (0% vs. 9% in non-progressors, p=.05) or GATA2 variants. Cytogenetic abnormalities were most frequent at the time of MN progression in 83% of cases, with chr. 7 alterations present in 47% of cases (-7, 35%; del(7q),12%), followed by complex karyotype (CK, 13%), involving chr.7 in 75% of cases. By comparison, -7/del(7q) are present in 7.5% of cases of our internal cohort of primary MN (p=.0001), but no differences in -7 and del7q distribution were seen. A total of 148 somatic variants (myeloid and HLA panels) were found at the time of evolution in 34/38 sMN pts, with an average of 4.4 mutations/patient. ASXL1 (29% vs 14%, p=.02) and SETBP1 (15% vs 3%, p=.005) hits were more frequent in evolved cases while TET2 and TP53 mutations were less common as compared with pMN. Of note, sMN pts with CK harbored ASXL1 and TP53 mutations in 50% of cases. In a cross-sectional analysis of evolved cases studied at AA onset (n=17) and at myeloid evolution (n=35), somatic lesions in TET2, DNMT3A and ASXL1 genes were found in 5, 1 and 3 pts at baseline, respectively. If variants in TET2 and DNMT3A likely reflect antecedent CHIP, ASXL1 variants may have a role in driving myeloid progression as shown by the higher mutation rate in post AA cases. This hypothesis is further supported by the acquisition of subclonal chr7 abnormalities and by the overall higher clonal burden at sMN onset (median VAF 24% vs 43% respectively, p=.0001). When comparing pts with chr7 abnormalities with de novo counterpart, in sMN genes appeared most commonly mutated in ASXL1 (p=.02), SETBP1 (p=.0007), ETV6 (p=.02) and NF1 (p=.02), while TP53 mutations were less common.The intrinsic peculiarity of this -7/del(7q) sMN subset is also underlined by a different median survival time (12 vs 48 months in sMN vs pMN, respectively, p=.0002). The HLA mutational analysis available for 10 sMN cases showed the presence of somatic class I/II loci variants in 4/10 of progressors, including pts with chr7 abnormalities in 3/4 of cases. Of note, all class I HLA mutations were found in locus C. By comparison, in non-progressing AA pts HLA class I/II variants were found in 13% of pts. Our results demonstrate that AA progression to MN has distinct molecular characteristics. The presence of HLA mutations suggests that immune escape or immune selection may play a role, while the presence of GL predisposition variants shows that they not only may facilitate AA but also clonal evolution as described from classic congenital BMF. Disclosures Patel: Alexion: Other: educational speaker. Voso:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Carraway:Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); BMS: Consultancy, Other: Research support, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

What's new in the pathogenesis and treatment of therapy-related myeloid neoplasms

Blood ◽  
2021 ◽  
Author(s):  
Maria Teresa Voso ◽  
Giulia Falconi ◽  
Emiliano Fabiani
Keyword(s):  
Atomic Bomb ◽  
Therapeutic Option ◽  
Familial Cancer ◽  
Autoimmune Disorder ◽  
New Drugs ◽  
Cancer Genes ◽  
Curative Intent ◽  
Tp53 Mutations ◽  
Myeloid Neoplasms ◽  
Cytotoxic Treatment

Therapy-related myeloid neoplasms (t-MN) include diseases onsetting in patients treated with chemo- and/or radiotherapy for a primary cancer, or an autoimmune disorder. Genomic variants, in particular in familial cancer genes, may play a predisposing role. Recent advances in deep sequencing techniques have shed light on the pathogenesis of t-MN, identifying clonal hematopoiesis of indeterminate potential (CHIP) as a frequent first step in the multi-hit model of t-MN. CHIP is often detectable prior to any cytotoxic treatment, probably setting the fertile genomic background for secondary leukemogenesis. The evolution pattern towards t-MN is then a complex process, shaped by the type of cancer therapy, the aging process, and the individual exposures, that favor additional hits, such as the acquisition of TP53 mutations and unfavorable karyotype abnormalities. The pathogenesis of t-MN differs from MN associated with environmental exposure. Indeed, the genetic aberration patterns of MN developing in atomic bomb survivors show few mutations in classical DNA methylation genes, and a high prevalence of 11q and ATM alterations, together with TP53 mutations. Survival in t-MN is poor. In addition to the biology of t-MN, the patient's previous disease history and the remission status at t-MN diagnosis are significant factors contributing to unfavorable outcome. New drugs active in secondary leukemias include CPX-351, or venetoclax in combination with hypomethylating agents, monoclonal antibodies as magrolimab, or targeted drugs against pathogenic mutations. Allogeneic stem cell transplantation remains the best currently available therapeutic option with curative intent for fit patients with unfavorable genetic profiles.

scholarly journals High Levels of Chromosomal Copy Number Alterations and TP53 Mutations Correlate with Poor Outcome in Younger Breast Cancer Patients

2020 ◽  
Vol 190 (8) ◽  
pp. 1643-1656
Author(s):  
Ayla Koçak ◽  
Kerstin Heselmeyer-Haddad ◽  
Annette Lischka ◽  
Daniela Hirsch ◽  
David Fiedler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Breast Cancer Patients ◽  
Tp53 Mutations ◽  
Poor Outcome ◽  
Chromosomal Copy Number ◽  
Chromosomal Copy

scholarly journals Treatments targeting MDS genetics: a fool’s errand?

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 277-285 ◽  
Author(s):  
Amy E. DeZern
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Patient Outcomes ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Failure ◽  
Targeted Agents ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Improve Patient

Abstract The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure characteristically seen in patients. The heterogeneity of myelodysplastic syndrome pathobiology has historically posed a challenge to the development of newer therapies. Recent advances in molecular characterization of myelodysplastic syndromes are improving diagnostic accuracy, providing insights into pathogenesis, and refining therapeutic options for patients. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.

Age-Adjusted Telomere Length Is Not Associated with Variation in Hematological Parameters in Ageing Women

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3102-3102
Author(s):  
Isabelle Fleury ◽  
Sylvie Provost ◽  
Claude Belisle ◽  
Lambert Busque
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Telomere Length ◽  
Marrow Transplantation ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Telomere Maintenance ◽  
Hematological Parameter ◽  
Allogeneic Bone ◽  
Potential Biomarker

Abstract Background. Telomeres play a crucial role in maintaining physical integrity of chromosomes. In the absence of telomerase, telomere length (TL) shortens with each cell division up to a critical threshold where cellular senescence occurs. TL is inversely correlated with age, is longer in women than in men, and demonstrates a strong heritability. Normal blood counts are maintained through out life by an extraordinary number of cell divisions rendering telomere maintenance primordial to prevent stem cell exhaustion. In fact, some cases of bone marrow failure syndromes, such as aplastic anemia and dyskeratosis congenital, have been linked to mutation in the telomerase gene; and stressed hematopoiesis, such at it occurs during the first year following allogeneic bone marrow transplantation induces TL shortening. We hypothesized that individuals with shorter TL may have lower blood counts and a decreased bone marrow reserve. The evaluation of TL as a potential biomarker of ageing hematopoiesis is important in the context of bone marrow transplantation performed with increasingly old donors. Methods. We measured TL in 1583 women, predominantly aged over 60, all originating from 288 French-Canadian families using a real-time quantitative PCR method that measures the number of telomere repeats relatively to the copy number of a single copy number gene. Telomeres were adjusted for age. Pearson or Spearman correlations were used to determine association between age-adjusted TL (aTL) and hematological parameter according to, respectively, whether or not a normal distribution was observed for these data. A Bonferroni correction was further applied to set the statistical significance threshold. Results. aTL varied significantly between individuals of the cohort, but no correlation was detected with hemoglobin levels (−0,001; p=0,978), mean corpuscular volume (−0,031; p=0,403); leucocytes (0,055; p=0,139); neutrophils (0,078; p=0,036), monocytes, (0,059; p=0,113), eosinophils (−0,032; p=0,394) and platelets (0,030; p=0,428) counts. Conclusion. Based on our analysis, TL do not predict blood cells counts in ageing women and may not be a useful biomarker for donor selection. This could also suggest that there is a threshold beyond which TL has an effect on hematopoiesis and that point was not reached in our cohort.

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