Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia
Allan Beke
(1)
,
Lucie Laplane
(2, 1)
,
Julie Riviere
(1)
,
Qin Yang
(3)
,
Miguel Torres-Martin
(3)
,
Thibault Dayris
(4)
,
Philippe Rameau
(4)
,
Veronique Saada
(5, 6)
,
Chrystèle Bilhou-Nabera
(7)
,
Ana Hurtado
(8)
,
Larissa Lordier
(1, 4)
,
William Vainchenker
(1)
,
Maria Figueroa
(3)
,
Nathalie Droin
(1)
,
Eric Solary
(1)
1
Dynamo -
Dynamique moléculaire de la transformation hématopoïétique
2 IHPST - Institut d'Histoire et de Philosophie des Sciences et des Techniques
3 UMMSM - University of Miami Leonard M. Miller School of Medicine
4 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
5 IGR - Institut Gustave Roussy
6 Génétique (Biologie pathologie)
7 CHU Saint-Antoine [AP-HP]
8 Hospital Morales Meseguer, Murcia, Spain
2 IHPST - Institut d'Histoire et de Philosophie des Sciences et des Techniques
3 UMMSM - University of Miami Leonard M. Miller School of Medicine
4 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
5 IGR - Institut Gustave Roussy
6 Génétique (Biologie pathologie)
7 CHU Saint-Antoine [AP-HP]
8 Hospital Morales Meseguer, Murcia, Spain
Lucie Laplane
- Fonction : Auteur
- PersonId : 11434
- IdHAL : lucie-laplane
- ORCID : 0000-0003-0185-3323
- IdRef : 175900078
Miguel Torres-Martin
- Fonction : Auteur
- PersonId : 818921
- ORCID : 0000-0003-1589-8936
Ana Hurtado
- Fonction : Auteur
- PersonId : 763343
- ORCID : 0000-0001-7089-9670
William Vainchenker
- Fonction : Auteur
- PersonId : 757193
- ORCID : 0000-0003-4705-202X
- IdRef : 084304685
Nathalie Droin
- Fonction : Auteur
- PersonId : 770388
- IdHAL : nathalie-droin-44106
- ORCID : 0000-0002-6099-5324
- IdRef : 176330593
Eric Solary
- Fonction : Auteur
- PersonId : 757151
- IdHAL : eric-solary
- ORCID : 0000-0002-8629-1341
- IdRef : 050500031
Résumé
The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34+ cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS(G12D) mutation. CD34+ cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS(G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
Domaines
Sciences du Vivant [q-bio]Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Résumé |
en
The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34+ cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS(G12D) mutation. CD34+ cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS(G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
|
Titre |
en
Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia
|
Auteur(s) |
Allan Beke
1
, Lucie Laplane
2, 1
, Julie Riviere
1
, Qin Yang
3
, Miguel Torres-Martin
3
, Thibault Dayris
4
, Philippe Rameau
4
, Veronique Saada
5, 6
, Chrystèle Bilhou-Nabera
7
, Ana Hurtado
8
, Larissa Lordier
1, 4
, William Vainchenker
1
, Maria Figueroa
3
, Nathalie Droin
1
, Eric Solary
1
1
Dynamo -
Dynamique moléculaire de la transformation hématopoïétique
( 1057805 )
- Institut Gustave Roussy, Pavillon de recherche 1, 114 rue Edouard-Vaillant, 94805 Villejuif
- France
2
IHPST -
Institut d'Histoire et de Philosophie des Sciences et des Techniques
( 1064581 )
- 13, rue du Four 75006 PARIS
- France
3
UMMSM -
University of Miami Leonard M. Miller School of Medicine
( 116558 )
- Miami, Florida, USA
- États-Unis
4
AMMICa -
Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
( 1051142 )
- Gustave-Roussy
114, rue Édouard Vaillant
94805 Villejuif
- France
5
IGR -
Institut Gustave Roussy
( 156104 )
- 114, rue Édouard-Vaillant 94805 Villejuif Cedex -France
- France
6
Génétique (Biologie pathologie)
( 165205 )
- Gustave Roussy. 114, rue Édouard-Vaillant 94805 Villejuif Cedex -France
- France
7
CHU Saint-Antoine [AP-HP]
( 454982 )
- 184, rue du Faubourg Saint-Antoine
75571 Paris cedex 12
- France
8
Hospital Morales Meseguer, Murcia, Spain
( 333468 )
-
- France
|
Date de publication |
2020-01-01
|
Langue du document |
Anglais
|
Nom de la revue |
|
Volume |
105
|
Numéro |
1
|
Page/Identifiant |
112-123
|
Audience |
Internationale
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Domaine(s) |
|
DOI | 10.3324/haematol.2018.208488 |
Pubmed Id | 31048357 |
PubMed Central | PMC6939510 |
Origine :
Fichiers produits par l'(les) auteur(s)
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