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Analysis of nonleuk...
Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones
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- Saeed, Borhan R. (författare)
- Heidelberg University
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- Manta, Linda (författare)
- Heidelberg University
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- Raffel, Simon (författare)
- German Cancer Research Centre,Heidelberg University
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- Pyl, Paul Theodor (författare)
- Lund University,Lunds universitet,Bröstcancer Proteogenomik,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breast cancer Proteogenomics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,European Molecular Biology Laboratory Heidelberg
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- Buss, Eike C. (författare)
- Heidelberg University
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- Wang, Wenwen (författare)
- Heidelberg University,Fudan University,Fudan University Shanghai Cancer Center (FUSCC)
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- Eckstein, Volker (författare)
- Heidelberg University
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- Jauch, Anna (författare)
- Heidelberg University
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- Trumpp, Andreas (författare)
- German Cancer Research Centre
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- Huber, Wolfgang (författare)
- European Molecular Biology Laboratory Heidelberg
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- Ho, Anthony D. (författare)
- Heidelberg University
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- Lutz, Christoph (författare)
- Praxis für Hämatologie und Onkologie, Koblenz,Heidelberg University
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(creator_code:org_t)
- 2021-01-18
- 2021
- Engelska.
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:11, s. 2825-2838
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- To acquire a better understanding of clonal evolution of acute myeloid leukemia (AML) and to identify the clone(s) responsible for disease recurrence, we have comparatively studied leukemia-specific mutations by whole-exome-sequencing (WES) of both the leukemia and the nonleukemia compartments derived from the bone marrow of AML patients. The T-lymphocytes, B-lymphocytes and the functionally normal hematopoietic stem cells (HSC), that is, CD34+/CD38−/ALDH+ cells for AML with rare-ALDH+ blasts (<1.9% ALDH+ cells) were defined as the nonleukemia compartments. WES identified 62 point-mutations in the leukemia compartment derived from 12 AML-patients at the time of diagnosis and 73 mutations in 3 matched relapse cases. Most patients (8/12) showed 4 to 6 point-mutations per sample at diagnosis. Other than the mutations in the recurrently mutated genes such as DNMT3A, NRAS and KIT, we were able to identify novel point-mutations that have not yet been described in AML. Some leukemia-specific mutations and cytogenetic abnormalities including DNMT3A(R882H), EZH2(I146T) and inversion(16) were also detectable in the respective T-lymphocytes, B-lymphocytes and HSC in 5/12 patients, suggesting that preleukemia HSC might represent the source of leukemogenesis for these cases. The leukemic evolution was reconstructed for five cases with detectable preleukemia clones, which were tracked in follow-up and relapse samples. Four of the five patients with detectable preleukemic mutations developed relapse. The presence of leukemia-specific mutations in these nonleukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long-term cure.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- acute myeloid leukemia (AML)
- clonal evolution
- hematopoietic stem cells (HSC)
- relapse
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- art (ämneskategori)
- ref (ämneskategori)
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- Av författaren/redakt...
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Saeed, Borhan R.
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Manta, Linda
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Raffel, Simon
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Pyl, Paul Theodo ...
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Buss, Eike C.
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Wang, Wenwen
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Eckstein, Volker
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Jauch, Anna
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Trumpp, Andreas
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Huber, Wolfgang
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Ho, Anthony D.
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Lutz, Christoph
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visa färre...
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