Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia.
OBJECTIVE
Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease.


METHODS
Cross-sectional study of patients referred during 2007 through 2009.


METHODS
Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation-sensitive gel electrophoresis and agarose gel electrophoresis techniques.


RESULTS
Of 131 patients, 23 (17.5%) (0.95% CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4%), M3 (21.7%) and M5 (17.4%). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0%) samples (0.95% CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35%), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12%). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012).


CONCLUSIONS
Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations.
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
Vahid
V
Pazhakh
Farhad
F
Zaker
Kamran
K
Alimoghaddam
Farzaneh
F
Atashrazm
D003430:Cross-Sectional Studies; D005260:Female; D016236:Genes, fms; D006801:Humans; D007492:Iran; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3
J Biol Chem. 2002 Dec 13;277(50):48234-40
12374805
Methods Mol Biol. 2011;688:v
20954420
Cancer Cell. 2004 May;5(5):465-75
15144954
N Engl J Med. 2005 Jan 20;352(3):291-2
15659732
Blood. 2003 Feb 1;101(3):837-45
12393383
Arch Iran Med. 2010 Jan;13(1):21-5
20039765
Leuk Res. 2007 Jan;31(1):109-11
16678898
Biochemistry. 1979 Jul 24;18(15):3381-6
465478
Blood. 2006 May 15;107(10):4011-20
16455956
N Engl J Med. 2005 Jan 20;352(3):254-66
15659725
J Clin Oncol. 2004 Feb 15;22(4):624-33
14726504
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10325-9
8234293
J Mol Diagn. 2006 May;8(2):254-9
16645213
Blood. 2005 Dec 1;106(12):3733-9
16076867
Leukemia. 2002 Feb;16(2):196-202
11840285
J Clin Oncol. 2002 Aug 1;20(15):3254-61
12149299
Hematol J. 2003;4(1):31-40
12692518
Blood. 1999 May 1;93(9):3074-80
10216104
Blood. 2005 Dec 1;106(12):3740-6
16051734
Leukemia. 2003 Sep;17(9):1738-52
12970773
Blood. 2001 Sep 1;98(5):1312-20
11520776
Leukemia. 1998 Sep;12(9):1333-7
9737679
Biochemistry. 1989 Nov 28;28(24):9495-501
2482073
Blood. 2005 Oct 15;106(8):2854-61
15994285
Blood. 2002 Dec 15;100(13):4372-80
12393388
Blood. 2002 Oct 15;100(8):2717-23
12351377
Cell Cycle. 2002 Jan;1(1):75-81
12429912
Leuk Res. 2007 Sep;31(9):1205-11
17306368
Leukemia. 2005 Aug;19(8):1479-82
15973451
Biochem Biophys Res Commun. 1991 Jun 14;177(2):673-8
2049089
Blood. 2002 Sep 1;100(5):1532-42
12176867
J Biol Chem. 1988 Sep 15;263(26):12824-7
3417636
Exp Cell Res. 2002 Jun 10;276(2):233-41
12027453
Blood. 2005 Dec 1;106(12):3747-54
16109776
Blood. 2005 Aug 1;106(3):899-902
15831697