Transcriptomic rationale for synthetic lethality-targeting ERCC1 and CDKN1A in chronic myelomonocytic leukaemia.
Authors
Hurtado, ALuengo-Gil, G
Chen-Liang, T
Amaral, Fabio
Batta, Kiran
Palomo, L
Lumbreras, E
Przychodzen, B
Caparros, E
Amigo, M
Dıez-Campelo, M
Zamora, L
Salido Fierrez, E
Maciejewski, J
Ortuño, F
Vicente, V
Del Canizo, M
Sole, F
Ferrer-Marin, F
Wiseman, Daniel H
Jerez, A
Affiliation
Haematology Department, Hospital Morales Meseguer, IMIB, Murcia, SpainIssue Date
2018-05-24
Metadata
Show full item recordAbstract
Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases. We found BAP1 and PARP1 down-regulation to be specific to CMML compared with other related disorders. Chromatin-regulator mutated cases showed decreased BAP1 dosage. We validated a significant over-expression of the double strand break-fidelity genes CDKN1A and ERCC1, independent of promoter methylation and associated with chemorefractoriness. In addition, patients bearing mutations in the splicing component SRSF2 displayed numerous aberrant splicing events in DNA repair genes, with a quantitative predominance in the single strand break pathway. Our results highlight potential targets in this disease, which currently has few therapeutic options.Citation
Transcriptomic rationale for synthetic lethality-targeting ERCC1 and CDKN1A in chronic myelomonocytic leukaemia. 2018, Br J HaematolJournal
British Journal of HaematologyDOI
10.1111/bjh.15408PubMed ID
29797327Type
ArticleLanguage
enISSN
1365-2141ae974a485f413a2113503eed53cd6c53
10.1111/bjh.15408
Scopus Count
Collections
Related articles
- Myelodysplastic syndromes without peripheral monocytosis but with evidence of marrow monocytosis share clinical and molecular characteristics with CMML.
- Authors: Schuler E, Frank F, Hildebrandt B, Betz B, Strupp C, Rudelius M, Aul C, Schroeder T, Gattermann N, Haas R, Germing U
- Issue date: 2018 Feb
- Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome?
- Authors: Michaux JL, Martiat P
- Issue date: 1993 Jan
- Mutations in chronic myelomonocytic leukemia and their prognostic relevance.
- Authors: Jian J, Qiao Y, Li Y, Guo Y, Ma H, Liu B
- Issue date: 2021 Sep
- The detection of SRSF2 mutations in routinely processed bone marrow biopsies is useful in the diagnosis of chronic myelomonocytic leukemia.
- Authors: Federmann B, Abele M, Rosero Cuesta DS, Vogel W, Boiocchi L, Kanz L, Quintanilla-Martinez L, Orazi A, Bonzheim I, Fend F
- Issue date: 2014 Dec
- Chronic myelomonocytic leukemia: The role of bone marrow biopsy immunohistology.
- Authors: Orazi A, Chiu R, O'Malley DP, Czader M, Allen SL, An C, Vance GH
- Issue date: 2006 Dec