Clonal hierarchy of main molecular lesions in acute myeloid
leukaemia

J 2020

Clonal hierarchy of main molecular lesions in acute myeloid leukaemia

HERUDKOVÁ, Zdeňka, Martin ČULEN, Adam FOLTA, Ivana JEŽÍŠKOVÁ, Jana CERNA et. al.

Basic information

Original name

Clonal hierarchy of main molecular lesions in acute myeloid leukaemia

Authors

HERUDKOVÁ, Zdeňka (203 Czech Republic, belonging to the institution), Martin ČULEN (703 Slovakia, belonging to the institution), Adam FOLTA (203 Czech Republic), Ivana JEŽÍŠKOVÁ (203 Czech Republic), Jana CERNA (203 Czech Republic), Tomáš LOJA (703 Slovakia, belonging to the institution), Nikola TOM (203 Czech Republic, belonging to the institution), Jiri SMEJKAL (203 Czech Republic), Lukáš SEMERÁD (203 Czech Republic), Dana DVOŘÁKOVÁ (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution) and Zdeněk RÁČIL (203 Czech Republic, guarantor, belonging to the institution)

Edition

British journal of haematology, Hoboken, Wiley-Blackwell, 2020, 0007-1048

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.998

RIV identification code

RIV/00216224:14110/20:00115741

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1111/bjh.16341

UT WoS

000501700400001

Keywords in English

acute myeloid leukaemia; mutations; relapse; patient-derived xenograft; clonality

Abstract

V originále

Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML-associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient-derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late-acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia-transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non-specific order of acquisition.

Links

MUNI/A/1105/2018, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VI (Acronym: VýDiTeHeMA VI)

Investor: Masaryk University, Category A

NV15-25809A, research and development project

Name: Národní program studia mutací a klonality leukemických buněk u pacientů s akutní myeloidní leukémií

Citovat

HERUDKOVÁ, Zdeňka, Martin ČULEN, Adam FOLTA, Ivana JEŽÍŠKOVÁ, Jana CERNA, Tomáš LOJA, Nikola TOM, Jiri SMEJKAL, Lukáš SEMERÁD, Dana DVOŘÁKOVÁ, Jiří MAYER and Zdeněk RÁČIL. Clonal hierarchy of main molecular lesions in acute myeloid leukaemia. British journal of haematology. Hoboken: Wiley-Blackwell, 2020, vol. 190, No 4, p. 562-572. ISSN 0007-1048. Available from: https://dx.doi.org/10.1111/bjh.16341.

@article{1660276,
   author = {Herudková, Zdeňka and Čulen, Martin and Folta, Adam and Ježíšková, Ivana and Cerna, Jana and Loja, Tomáš and Tom, Nikola and Smejkal, Jiri and Semerád, Lukáš and Dvořáková, Dana and Mayer, Jiří and Ráčil, Zdeněk},
   article_location = {Hoboken},
   article_number = {4},
   doi = {http://dx.doi.org/10.1111/bjh.16341},
   keywords = {acute myeloid leukaemia; mutations; relapse; patient-derived xenograft; clonality},
   language = {eng},
   issn = {0007-1048},
   journal = {British journal of haematology},
   title = {Clonal hierarchy of main molecular lesions in acute myeloid leukaemia},
   url = {https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.16341},
   volume = {190},
   year = {2020}
}

TY  - JOUR
ID  - 1660276
AU  - Herudková, Zdeňka - Čulen, Martin - Folta, Adam - Ježíšková, Ivana - Cerna, Jana - Loja, Tomáš - Tom, Nikola - Smejkal, Jiri - Semerád, Lukáš - Dvořáková, Dana - Mayer, Jiří - Ráčil, Zdeněk
PY  - 2020
TI  - Clonal hierarchy of main molecular lesions in acute myeloid leukaemia
JF  - British journal of haematology
VL  - 190
IS  - 4
SP  - 562-572
EP  - 562-572
PB  - Wiley-Blackwell
SN  - 00071048
KW  - acute myeloid leukaemia
KW  - mutations
KW  - relapse
KW  - patient-derived xenograft
KW  - clonality
UR  - https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.16341
L2  - https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.16341
N2  - Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML-associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient-derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late-acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia-transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non-specific order of acquisition.
ER  -

HERUDKOVÁ, Zdeňka, Martin ČULEN, Adam FOLTA, Ivana JEŽÍŠKOVÁ, Jana CERNA, Tomáš LOJA, Nikola TOM, Jiri SMEJKAL, Lukáš SEMERÁD, Dana DVOŘÁKOVÁ, Jiří MAYER and Zdeněk RÁČIL. Clonal hierarchy of main molecular lesions in acute myeloid leukaemia. \textit{British journal of haematology}. Hoboken: Wiley-Blackwell, 2020, vol.~190, No~4, p.~562-572. ISSN~0007-1048. Available from: https://dx.doi.org/10.1111/bjh.16341.

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