Molecular pathogenesis of disease progression in MLL-rearranged AML.
Animals
Cell Proliferation
/ genetics
Disease Progression
Down-Regulation
/ genetics
GTP-Binding Proteins
/ genetics
Gene Expression Regulation, Leukemic
/ genetics
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Leukemia, Myeloid, Acute
/ genetics
Mice
Mice, Inbred C57BL
Mutation
/ genetics
Myeloid-Lymphoid Leukemia Protein
/ genetics
Oncogene Proteins, Fusion
/ genetics
Up-Regulation
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
26
01
2018
accepted:
07
08
2018
revised:
25
06
2018
pubmed:
14
9
2018
medline:
21
5
2019
entrez:
14
9
2018
Statut:
ppublish
Résumé
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.
Identifiants
pubmed: 30209403
doi: 10.1038/s41375-018-0253-3
pii: 10.1038/s41375-018-0253-3
pmc: PMC6462875
doi:
Substances chimiques
KMT2A protein, human
0
Oncogene Proteins, Fusion
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
GTP-Binding Proteins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
612-624Subventions
Organisme : NHLBI NIH HHS
ID : K24 HL077522
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL082983
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR019391
Pays : United States
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