Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this issue of Blood, Watanabe-Okochi and colleagues use a mouse bone marrow transplantation model to demonstrate that mutant alleles of AML1 (RUNX1) can initiate a myelodysplastic syndrome (MDS) that progresses to acute myelogenous leukemia (AML) in association with overexpression of Evi1.
 ...
PMID:AML1 and Evi1: coconspirators in MDS/AML? 1819 4

In this study, we analyzed the roles for AML1/RUNX1 in the regulation of the c-mpl promoter. Wild-type AML1 activated the c-mpl promoter through the proximal AML-binding site in luciferase assays using 293T and HeLa cells. In accord with this result, electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that AML1 bound to this site. Next, we analyzed the function of AML1 using a mutant of AML1 lacking the C terminus (AML1dC), which was originally found in a patient with myelodysplastic syndromes. AML1dC dominant-negatively suppressed transcriptional activity of wild-type AML1. However, unexpectedly, AML1dC-transduced murine c-Kit(+)Sca1(+)Lineage(-) cells expressed c-mpl mRNA and c-Mpl protein more abundantly than mock-transduced cells, which led to the enhanced thrombopoietin-mediated proliferation. Moreover, when AML1dC was induced to express during the development of hematopoietic cells from embryonic stem (ES) cells, AML1dC augmented the c-Mpl expression on hematopoietic stem/progenitor cells. Furthermore, we found that early hematopoietic cells that derived from AML1(+/-) ES cells expressed c-Mpl more intensely than those that developed from wild-type ES cells. In contrast, AML1dC hardly affected c-Mpl expression and maturation of megakaryocytes. As for the mechanism of the different roles of AML1 in the regulation of the c-mpl promoter, we found that AML1 forms a complex with a transcription repressor mSin3A on the c-mpl promoter in hematopoietic stem/progenitor cells, although it forms a complex with a transcription activator p300 on the same promoter in megakaryocytic cells. Together, these data indicate that AML1 can regulate the c-mpl promoter both positively and negatively by changing the binding partner according to cell types.
 ...
PMID:AML1/RUNX1 works as a negative regulator of c-Mpl in hematopoietic stem cells. 1868 90

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.
 ...
PMID:Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. 1872 28

It is known that bone marrow is a sensitive organ to ionizing radiation, and many patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) have been diagnosed in radiation-treated cases and atomic bomb survivors in Hiroshima and Nagasaki. The AML1/RUNX1 gene has been known to be frequently mutated in MDS/AML patients among atomic bomb survivors and radiation therapy-related MDS/AML patients. In this study, we investigated the AML1 mutations in radiation-exposed patients with MDS/AML among the residents near the Semipalatinsk Nuclear Test Site (SNTS), where the risk of solid cancers and leukemias was increased due to the radiation effects. AML1 mutations were identified in 7 (39%) of 18 radiation-exposed MDS/AML patients. In contrast, no AML1 mutation was found in 13 unexposed MDS/AML cases. The frequency of AML1 mutations in radiation-exposed patients with MDS/AML was significantly higher compared with unexposed patients (p < 0.05).We also found a significant correlation between individual estimated doses and AML1 mutations (p < 0.05). Considering these results, AML1 point mutations might be a useful biomarker that differentiates radio-induced MDS/AML from spontaneous MDS/AML.
 ...
PMID:High frequency of AML1/RUNX1 point mutations in radiation-associated myelodysplastic syndrome around Semipalatinsk nuclear test site. 1872 45

RUNX1-EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1-EVI1 has oncogenic potentials through dominant-negative effect over wild-type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP-1, suppression of TGF-beta-mediated growth inhibition and repression of C/EBPalpha. Runx1-EVI1 heterozygous knock-in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1-/- mice do, indicating that RUNX1-EVI1 dominantly suppresses functions of wild-type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1-EVI1, and a Runx1-EVI1 knock-in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1-EVI1 plays indispensable roles in leukemogenesis of t(3;21)-positive leukemia. Major leukemogenic effect of RUNX1-EVI1 is mainly through histone deacetyltransferase recruitment via C-terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1-EVI1-expressing leukemia.
 ...
PMID:Role of the RUNX1-EVI1 fusion gene in leukemogenesis. 1901 45

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML) that is characterized by peculiar clinical and biologic features, including severe hemorrhagic diathesis, specific recurrent chromosomal aberration, and distinct morphologic features with predominant pathologic promyelocytes. A reciprocal translocation involving chromosomes 15 and 17, t(15;17)(q22;q21), is a characteristic feature of APL that represents approximately 5-8% of AML. The rearranged gene created by this translocation encodes a chimeric protein PML-RARA that is a transcriptional repressor. In contrast to other AML subtypes, APL is particularly sensitive to treatment with all trans-retinoic acid (ATRA) combined with chemotherapy, converting this once fatal leukemia to a highly curable disease. Nonetheless, therapy-related myelodysplastic syndrome-acute myelogenous leukemia (t-MDS/AML) has been reported as a rare complication of chemotherapy in APL. Of 30 APL cases described as t-MDS/AML in the literature, only 1 case relapsed as acute leukemia with t(3;21)(q26;q22). Here we describe a rare case of APL relapsing as secondary AML with t(3;21)(q26;q22) and clinically characterize this patient using the RUNX1 (previously AML1)-MDS1-EVI1 fusion transcript (with follow-up for 55 months), and review the relevant literature.
 ...
PMID:Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EVI1 fusion transcript. 1902 86

To understand the cytogenetic mechanisms responsible for multiple RUNX1 gene copy numbers in hematologic malignancies, we analyzed the chromosomal and molecular cytogenetic findings in bone marrow or peripheral blood samples of individuals who were diagnosed with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphoblastic leukemia (ALL). Included in the analysis were 113 consecutive samples received in our laboratory between January 2005 and June 2007. Bone marrow and/or peripheral blood samples were characterized using conventional G-banding techniques and fluorescent in situ hybridization (FISH) techniques with commercially available RUNX1/RUNX1T1 or ETV6/RUNX1 dual-color fusion probes. Eighty-one (72%) of the 113 samples showed an abnormal karyotype and/or abnormal FISH results. Eight of these had, by interphase FISH, RUNX1/RUNX1T1 or RUNX1/ETV6 fusion, and 19 had three or more RUNX1 signals not related to fusion with RUNX1T1 or ETV6 gene. Of the 19 cases with multiple RUNX1 gene signals, 5 had high-level RUNX1 amplification--defined as 5 or more RUNX1 signals in interphase cells--whereas the remaining 14 had 3-4 RUNX1 signals. Four of the five tumors with high-level RUNX1 amplification were myeloid disorders--three cases of AML and one case of MDS. The karyotypes of tumors with high-level amplification of RUNX1 were significantly characterized by the presence of marker chromosomes that harbored extra copies of the RUNX1 gene compared with tumors that had three to four RUNX1 gene signals (P=0.026, Fisher's exact test). Our findings show that high-level RUNX1 amplification, especially in myeloid disorders, often results from marker chromosomes harboring extra copies of the RUNX1 gene . This suggests that amplification of RUNX1 in these tumors may be secondary to a previous rearrangement of 21q22, which later evolved into a complex marker chromosome as part of tumor progression.
 ...
PMID:Marker chromosomes are a significant mechanism of high-level RUNX1 gene amplification in hematologic malignancies. 1916 8

RUNX1T1/RUNX1 (formerly ETO/AML1) is a molecular marker that is usually associated with a favorable outcome in both pediatric and adult patients with acute myeloid leukemia (AML). We describe a 10-year-old girl with AML associated with an RUNX1T1/RUNX1 fusion. The patient's karyotype at the time of diagnosis was 46,X,-X,t(4;21;8)(q25;q22;q22),+6. She had an early relapse while being treated on a standard protocol and had significant difficulty in attaining a second remission. She subsequently underwent a matched related donor bone marrow transplant, but a second bone marrow relapse with extensive extramedullary disease followed on day +199. Cytogenetic analysis at second relapse showed evidence of clonal evolution in the form of a highly complex karyotype with numeric and structural abnormalities in addition to the t(4;21;8) and trisomy 6 detected in the diagnostic sample. Trisomy 6 is an uncommon cytogenetic abnormality in myeloid diseases. As a sole abnormality, it has been associated mainly with myelodysplastic syndrome and AML. The presence of this novel variant of t(8;21)(q22;q22) associated with trisomy 6 may have abrogated the usual favorable prognosis associated with RUNX1T1/RUNX1 in AML.
 ...
PMID:Poor outcome in a pediatric patient with acute myeloid leukemia associated with a variant t(8;21) and trisomy 6. 1916 12

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms defined by morphologic dysplasia, peripheral cytopenia and clonal instability with enhanced risk of transformation into acute myeloid leukemia. The prognosis and clinical picture in MDS vary depending on patient-related factors (age, gender, comorbidity), the disease variant, cell types affected and genes involved in the malignant process. In fact, more and more data suggest that cytogenetic and molecular defects and gene variants are associated with the clinical course and prognosis in MDS. Although certain molecular defects are indicative of distinct cytogenetic abnormalities, others represent point mutations in critical target genes (RUNX1, N-RAS, JAK2, KIT, others) and sometimes are associated with a particular type of MDS, an overlap disease, a co-existing hematopoietic neoplasm or disease progression. Although most are somatic mutations, germ line mutations and gene polymorphisms have also been described in MDS. Some of these mutations may influence the natural course of disease, iron accumulation or disease progression. The present article provides a summary of our current knowledge about molecular and genetic markers in MDS, with special reference to their potential prognostic and therapeutic implications.
 ...
PMID:Update on genetic and molecular markers associated with myelodysplastic syndromes. 1926 96

AML1/RUNX1 point mutations have been identified in myelodysplastic syndrome (MDS) and MDS-related acute myeloid leukemia (AML), or MDS/AML, and are distributed throughout the full length of AML1/RUNX1. Gene mutation is proposed to be one of the disease-defining genetic abnormalities of MDS/AML. Most of the mutants lose trans-activation potential, which leads to a loss of normal function indicating that AML1/RUNX1 dysfunction is one of the major pathogenic mechanisms of MDS/AML. However, N-terminal in-frame mutations (Ni-type) and C-terminal truncated mutations (Ct-type) of AML1/RUNX1 show a dominant-negative effect on the trans-activation activity, suggesting that these types of mutants may have some oncogenic potential in addition to the loss of normal function. The patients with Ni-type mutations have hypoplastic marrows with other genetic abnormalities, whereas the patients with Ct-type mutations display hyperplastic marrows without other mutations. Although biological analysis using a mouse bone marrow transplantation model transduced with Ni-type of D171N or Ct-type of S291fsX300 mutants has partially confirmed the oncogenic ability of AML1 mutants, it could not explain the mutant specific clinical features of MDS/AML. Biological analysis using human CD34(+) cells revealed that the two types exhibited distinct molecular mechanisms. Ni-type shows differentiation block without cell growth, but additional BMI-1-expression resulted in increased blastic cells. In contrast, Ct-type itself has proliferation ability. Thus, AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability.
 ...
PMID:Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations. 1933 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>