Point Mutations in the AML1/RUNX1 Gene Associated with Myelodysplastic Syndrome

2005 ◽  
Vol 15 (3) ◽  
pp. 183-196 ◽  
Author(s):  
Hironori Harada ◽  
Yuka Harada
Keyword(s):  
Myelodysplastic Syndrome ◽  
Point Mutations ◽  
Runx1 Gene

High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2316-2324 ◽  
Author(s):  
Hironori Harada ◽  
Yuka Harada ◽  
Hiromasa Niimi ◽  
Taiichi Kyo ◽  
Akiro Kimura ◽  
...  
Keyword(s):  
Dna Binding ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Driving Forces ◽  
Point Mutations ◽  
Terminal Region ◽  
Refractory Anemia ◽  
Binding Potential ◽  
Runx1 Gene ◽  
High Incidence

Abstract A high incidence of somatically acquired point mutations in the AML1/RUNX1 gene has been reported in poorly differentiated acute myeloid leukemia (AML, M0) and in radiation-associated and therapy-related myelodysplastic syndrome (MDS) or AML. The vast majority of AML1 mutations identified in these diseases were localized in the amino (N)–terminal region, especially in the DNA-binding Runt homology domain. In this report, we show that AML1 point mutations were found in 26 (23.6%) of 110 patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined these 3 disease categories as MDS/AML). Among them, 9 (8.2%) mutations occurred in the carboxy (C)–terminal region, which were exclusively found in MDS/AML and were strongly correlated with sporadic MDS/AML. All patients with MDS/AML with an AML1 mutation expressed wild-type AML1 protein and had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lost trans-activation potential, regardless of their DNA binding potential. These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopathologic-genetic entity.

scholarly journals Abrogation of RUNX1 gene expression in de novo myelodysplastic syndrome with t(4;21)(q21;q22)

Haematologica ◽  
2011 ◽  
Vol 97 (4) ◽  
pp. 534-537 ◽  
Author(s):  
A. Rio-Machin ◽  
J. Menezes ◽  
A. Maiques-Diaz ◽  
X. Agirre ◽  
B. I. Ferreira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myelodysplastic Syndrome ◽  
De Novo ◽  
Runx1 Gene

scholarly journals High Frequency of AML1/RUNX1 Point Mutations in Radiation-Associated Myelodysplastic Syndrome Around Semipalatinsk Nuclear Test Site

2008 ◽  
Vol 49 (5) ◽  
pp. 549-555 ◽  
Author(s):  
Dinara ZHARLYGANOVA ◽  
Hironori HARADA ◽  
Yuka HARADA ◽  
Sergey SHINKAREV ◽  
Zhaxybay ZHUMADILOV ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
High Frequency ◽  
Point Mutations ◽  
Test Site ◽  
Nuclear Test ◽  
Semipalatinsk Nuclear Test Site

scholarly journals Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS- derived leukemia

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3022-3026 ◽  
Author(s):  
K Sugimoto ◽  
N Hirano ◽  
H Toyoshima ◽  
S Chiba ◽  
H Mano ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Nucleotide Sequencing ◽  
Polymorphism Analysis ◽  
P53 Gene Mutation ◽  
Ras Gene ◽  
P53 Gene Mutations

The p53 gene is currently thought to be a tumor suppressor gene, and its alterations have been suggested to be involved in the pathogenesis of several human malignancies, including some leukemias and lymphomas. We present here evidence for the possible involvement of p53 gene mutations in the myelodysplastic syndrome (MDS), although the incidence is relatively low. Forty-four patients with MDS and six patients with overt leukemias that developed from MDS were studied for p53 gene alterations using reverse transcriptase-polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Three patients with MDS (2 RAEB and 1 RAEB in T) had missense point mutations in the conserved regions of the p53 coding sequence. Furthermore, expression of the wild-type p53 mRNA was not detected in these three patients. The probable absence of normal p53 function in the three cases studied here suggests that alterations in the p53 gene may occasionally play a role in MDS. These three MDS patients with p53 gene mutations and an MDS-derived erythroleukemia cell line that we had previously reported to carry a p53 gene mutation showed no N-ras gene mutations, suggesting heterogeneity in the oncogenic mechanism of MDS.

Acquired somatic ATRX mutations in myelodysplastic syndrome associated with α thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2019-2026 ◽  
Author(s):  
David P. Steensma ◽  
Douglas R. Higgs ◽  
Chris A. Fisher ◽  
Richard J. Gibbons
Keyword(s):  
Myelodysplastic Syndrome ◽  
High Performance ◽  
Germ Line ◽  
Somatic Mosaicism ◽  
Point Mutations ◽  
Hematologic Malignancies ◽  
Gene Encoding ◽  
Linked Gene ◽  
Molecular Defects ◽  
Archival Dna

Abstract Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in 4 patients with the rare subtype of myelodysplastic syndrome (MDS) associated with α thalassemia (ATMDS). Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high-performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism. Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germ line ATRX mutations (ATR-X syndrome), but the hematologic abnormalities were much more severe in the patients with ATMDS than in the corresponding constitutional cases. In one ATMDS case where DNA samples from several time points were available, the proportion of ATRX-mutant subclones correlated with changes in the amount of hemoglobin H. This study strengthens the link between acquired, somatic ATRX mutations and ATMDS, illustrates how molecular defects associated with MDS and other hematologic malignancies masked by somatic mosaicism may be detected by DHPLC, and shows that additional factors increase the severity of the hematologic phenotype of ATRX mutations in ATMDS.

LOSS OF MULTIPLE POINT MUTATIONS OF RAS GENES ASSOCIATED WITH ACQUISITION OF CHROMOSOMAL ABNORMALITIES DURING DISEASE PROGRESSION IN MYELODYSPLASTIC SYNDROME

1991 ◽  
Vol 77 (2) ◽  
pp. 250-252 ◽  
Author(s):  
Toshitaro Nakagawa ◽  
Susumu Saitoh ◽  
Shion Imoto ◽  
Mitsuhiro Itoh ◽  
Masayoshi Tsutsumi ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Chromosomal Abnormalities ◽  
Point Mutations ◽  
Multiple Point ◽  
Ras Genes

scholarly journals Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS- derived leukemia

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3022-3026 ◽  
Author(s):  
K Sugimoto ◽  
N Hirano ◽  
H Toyoshima ◽  
S Chiba ◽  
H Mano ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Nucleotide Sequencing ◽  
Polymorphism Analysis ◽  
P53 Gene Mutation ◽  
Ras Gene ◽  
P53 Gene Mutations

Abstract The p53 gene is currently thought to be a tumor suppressor gene, and its alterations have been suggested to be involved in the pathogenesis of several human malignancies, including some leukemias and lymphomas. We present here evidence for the possible involvement of p53 gene mutations in the myelodysplastic syndrome (MDS), although the incidence is relatively low. Forty-four patients with MDS and six patients with overt leukemias that developed from MDS were studied for p53 gene alterations using reverse transcriptase-polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Three patients with MDS (2 RAEB and 1 RAEB in T) had missense point mutations in the conserved regions of the p53 coding sequence. Furthermore, expression of the wild-type p53 mRNA was not detected in these three patients. The probable absence of normal p53 function in the three cases studied here suggests that alterations in the p53 gene may occasionally play a role in MDS. These three MDS patients with p53 gene mutations and an MDS-derived erythroleukemia cell line that we had previously reported to carry a p53 gene mutation showed no N-ras gene mutations, suggesting heterogeneity in the oncogenic mechanism of MDS.

Generation of Novel Knockin Mouse Lines Harboring Leukemia-Associated Point Mutations at AML1/Runx1 Gene Locus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 465-465 ◽  
Author(s):  
Yoko Fukushime-Nakase ◽  
Mitsushige Nakao ◽  
Tohru Sugimoto ◽  
Tsukasa Okuda
Keyword(s):  
Transcription Factor ◽  
Gene Locus ◽  
Point Mutations ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Negative Effects ◽  
Runt Domain ◽  
Runx1 Gene ◽  
Acute Myelogenous

Abstract Acute Myeloid Leukemia 1 (AML1; also called as Runt-related transcription factor 1: Runx1) encodes the DNA binding subunit of Core-Binding Factor (CBF) transcription factor complex which plays pivotal roles in several phases of hematopoietic regulation, including initial development of definitive hematopoiesis. AML1 is known as a frequent target of leukemia-associated chromosomal translocations, where chimeric AML1 genes with strong dominant-negative effects against normal CBF function are produced. Recently, point-mutations of the AML1 gene locus have also been reported to associate with sporadic cases of acute myelogenous leukemia or myelodysplastic syndromes, and pedigrees of Familial Platelet Disorder with Predisposition to Acute Myelogenous Leukemia (FPD/AML). Hot spots of the mutations are confined to within the Runt domain, which is the signature-motif of the AML1 molecules localized near the N-terminus and is responsible for both sequence-specific DNA binding and hetero-dimerization with CBFβ subunit. Biochemical examinations have so far demonstrated that these mutants lose their function as a transcription factor and that most of them also have dominant-negative effects at some extent. Indeed, three-dimensional analyses of the Runt domain structure revealed that frequent sites of the mutation, such as, R80, R139, R174, or R177, were mapped at residues important for the DNA-contact of the molecule while mutations of these residues left AML1’s ability to associate with CBFβ being un-affected, thus providing a molecular basis of their biochemical characteristics. In contrast, however, biological properties of the mutations are mostly left to be elucidated. In order to define the biologic consequences of the point-mutations at Runx1 gene locus within the context of entire mouse, we introduced each of the point-mutations, including R139Q, R174Q, or R177Q, into mouse germline by means of a gene-knockin approach. Heterozygous mice for each of the mutations were born healthy and grew up fertile as far as they were kept under specific pathogen-free conditions similarly to their wild-type siblings or to control mouse lines harboring a knockin allele with wild-type cDNA of Runx1. These observations indicate that the dominant-negative effects of the mutations, if any present, are not that strong as is the case for the AML1-MTG8 (ETO) chimeric gene which leads to mid-gestational death when transmitted to one allele of mouse germline. In addition, in contrast to the knockin of the wild-type cDNA which results in minimal phenotype in the homozygous progeny, homozygous mice for the R174Q allele were embryonic-lethal just like the simple disruption of this gene, clearly indicating that this leukemia-associated one amino acid substitution, arginine-to-glutamine at the 174th residue, abolished its biologic function completely. We are generating homozygous progeny by breeding for R139Q and R177Q alleles to further define their biologic consequences. In addition, examinations are currently undertaken to analyze if the heterozygous mice manifest any phenotype resulted from haplo-insufficiency along with possible dominant-negative effects by these mutations. These knockin mice should contribute to better understanding of the molecular mechanisms of AML1/Runx1 activity in normal and leukemic hematopoiesis.

Somatic point mutations in RUNX1/CBFA2/AML1 are common in high-risk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia

2005 ◽  
Vol 74 (1) ◽  
pp. 47-53 ◽  
Author(s):  
David P. Steensma ◽  
Richard J. Gibbons ◽  
Ruben A. Mesa ◽  
Ayalew Tefferi ◽  
Douglas R. Higgs
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Point Mutations ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia
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