RUNX1 mutation and elevated FLT3 gene expression cooperates to induce inferior prognosis in cytogenetically normal acute myeloid leukemia patients.
Acute myeloid leukemia
FLT3
Mutations
Prognosis
RUNX1
Journal
Saudi journal of biological sciences
ISSN: 1319-562X
Titre abrégé: Saudi J Biol Sci
Pays: Saudi Arabia
ID NLM: 101543796
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
30
05
2021
revised:
02
07
2021
accepted:
04
07
2021
entrez:
1
9
2021
pubmed:
2
9
2021
medline:
2
9
2021
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is a bone marrow malignancy having multiple molecular pathways driving its progress. In recent years, the main causes of AML considered all over the world are genetic variations in cancerous cells. The RUNX1 and FLT3 genes are necessary for the normal hematopoiesis and differentiation process of hematopoietic stem cells into mature blood cells, therefore they are the most common targets for point mutations resulting in AML. We screened 32 CN-AML patients for FLT3-ITD (by Allele-specific PCR) and RUNX1 mutations (by Sanger sequencing). The FLT3 mRNA expression was assessed in all AML patients and its subgroups. Eight patients (25%) carried RUNX1 mutation (K83E) while three patients (9.37%) were found to have internal tandem duplications in FLT3 gene. The RUNX1 mutation data were correlated with clinical parameters and FLT3 gene expression profile. The RUNX1 mutations were observed to be significantly prevalent in older males. Moreover, RUNX1 and FLT3-mutated patients had lower complete remission rate, event-free survival rate, and lower overall survival rate than patients with wild-type RUNX1 and FLT3 gene. The RUNX1 and FLT3 mutant patients with up-regulated FLT3 gene expression showed even worse prognosis. Bradford Assay showed that protein concentration was down-regulated in RUNX1 and FLT3 mutants in comparison to RUNX1 and FLT3 wild-type groups. This study constitutes the first report from Pakistan reporting significant molecular mutation analysis of RUNX1 and FLT3 genes including FLT3 expression evaluation with follow-up. This provides an insight that aforementioned mutations are markers of poor prognosis but the study with a large AML cohort will be useful to further investigate their role in disease biology of AML.
Sections du résumé
BACKGROUND
BACKGROUND
Acute myeloid leukemia (AML) is a bone marrow malignancy having multiple molecular pathways driving its progress. In recent years, the main causes of AML considered all over the world are genetic variations in cancerous cells. The RUNX1 and FLT3 genes are necessary for the normal hematopoiesis and differentiation process of hematopoietic stem cells into mature blood cells, therefore they are the most common targets for point mutations resulting in AML.
METHODS
METHODS
We screened 32 CN-AML patients for FLT3-ITD (by Allele-specific PCR) and RUNX1 mutations (by Sanger sequencing). The FLT3 mRNA expression was assessed in all AML patients and its subgroups.
RESULTS
RESULTS
Eight patients (25%) carried RUNX1 mutation (K83E) while three patients (9.37%) were found to have internal tandem duplications in FLT3 gene. The RUNX1 mutation data were correlated with clinical parameters and FLT3 gene expression profile. The RUNX1 mutations were observed to be significantly prevalent in older males. Moreover, RUNX1 and FLT3-mutated patients had lower complete remission rate, event-free survival rate, and lower overall survival rate than patients with wild-type RUNX1 and FLT3 gene. The RUNX1 and FLT3 mutant patients with up-regulated FLT3 gene expression showed even worse prognosis. Bradford Assay showed that protein concentration was down-regulated in RUNX1 and FLT3 mutants in comparison to RUNX1 and FLT3 wild-type groups.
CONCLUSION
CONCLUSIONS
This study constitutes the first report from Pakistan reporting significant molecular mutation analysis of RUNX1 and FLT3 genes including FLT3 expression evaluation with follow-up. This provides an insight that aforementioned mutations are markers of poor prognosis but the study with a large AML cohort will be useful to further investigate their role in disease biology of AML.
Identifiants
pubmed: 34466057
doi: 10.1016/j.sjbs.2021.07.012
pii: S1319-562X(21)00585-4
pmc: PMC8381075
doi:
Types de publication
Journal Article
Langues
eng
Pagination
4845-4851Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Références
Blood. 2011 Feb 24;117(8):2348-57
pubmed: 21148331
J Pharmacol Exp Ther. 2007 Jan;320(1):266-73
pubmed: 17050781
Leukemia. 2003 Sep;17(9):1738-52
pubmed: 12970773
J Mol Diagn. 2003 May;5(2):96-102
pubmed: 12707374
Virol J. 2012 Jan 10;9:11
pubmed: 22234052
Biopolymers. 2006 Apr 15;81(6):428-39
pubmed: 16365849
J Exp Med. 2006 Feb 20;203(2):371-81
pubmed: 16446383
Br J Haematol. 2017 Nov;179(4):530-542
pubmed: 28653397
Leuk Lymphoma. 2005 Dec;46(12):1679-87
pubmed: 16263569
Nucleic Acids Res. 2011 Sep 1;39(17):e118
pubmed: 21727090
Blood. 2007 Jan 15;109(2):431-48
pubmed: 16960150
Cell. 2000 Jan 7;100(1):57-70
pubmed: 10647931
Hum Mutat. 2006 Aug;27(8):830-1
pubmed: 16835905
Leukemia. 2012 Jul;26(7):1527-36
pubmed: 22318449
Blood. 2002 Jul 1;100(1):59-66
pubmed: 12070009
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012 Dec;20(6):1312-5
pubmed: 23257423
Nat Rev Cancer. 2003 Sep;3(9):650-65
pubmed: 12951584
Blood. 2005 Jul 1;106(1):265-73
pubmed: 15769897
Cancer Res. 2007 Oct 1;67(19):9134-41
pubmed: 17909018
Blood Rev. 2019 Jul;36:70-87
pubmed: 31101526
J Clin Oncol. 2011 Apr 1;29(10):1364-72
pubmed: 21343560
Anal Biochem. 1976 May 7;72:248-54
pubmed: 942051
Arch Med Res. 2006 Aug;37(6):696-9
pubmed: 16824927
J Mol Biol. 2007 Jul 13;370(3):598-607
pubmed: 17524421
Biochem Cell Biol. 2006 Apr;84(2):243-9
pubmed: 16609705
Cell Rep. 2015 Aug 4;12(5):821-36
pubmed: 26212328
N Engl J Med. 2008 May 1;358(18):1909-18
pubmed: 18450602
Blood. 2009 Dec 17;114(26):5352-61
pubmed: 19808697
N Engl J Med. 2015 Sep 17;373(12):1136-52
pubmed: 26376137
Int J Biochem Cell Biol. 2005 Jun;37(6):1168-72
pubmed: 15778081
J Clin Oncol. 2012 Sep 1;30(25):3109-18
pubmed: 22753902
Gastroenterology. 2009 Mar;136(3):883-92
pubmed: 19121318