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

The KIT proto-oncogene encodes a tyrosine kinase receptor which plays a critical role in haemopoiesis. We have screened genomic DNA from bone marrow mononuclear cells of 46 patients with myelodysplasia (MDS) for mutations/deletions of exons 6, 13, 17, and 21 of the KIT gene (stem cell factor receptor) using polymerase chain reaction (PCR), polyacrylamide gel electrophoresis, and autoradiography to detect single-stranded conformational polymorphisms (SSCP). These exons include positions analogous to those mutated in the FMS gene (colony-stimulating factor-1 receptor) in myelodysplastic syndrome (MDS) and mutated/deleted in the Dominant White Spotting mouse (W locus) which results in macrocytic anaemia. Two different gel running conditions were used for each exon. Polymorphisms were identified only at 4 degrees C in exon 17 (three out of 44 MDS samples and two of 21 DNA samples from normal subjects), and in the non-coding region of exon 21 (five out of 34 MDS samples and seven out of 19 normals). Direct sequencing identified a G to A base change at nucleotide 3169 within exon 21, and a C to T change at position 2415 in exon 17. No conformational changes suggestive of mutations or deletions have been found to date, although we cannot rule out low frequency clonal abnormalities undetectable by our method, which has a sensitivity in our hands of approximately 5%. Polymorphisms occur frequently in the KIT gene. Together with this study, a total of five have been described.
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PMID:Two new polymorphisms but no mutations of the KIT gene in patients with myelodysplasia at positions corresponding to human FMS and murine W locus mutational hot spots. 769 8

It has been supposed in de novo AML that malignant transformation occurs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regularly occur at the level of stem cells. These cells can be discriminated by function and specific surface molecules. CD34, a glycophosphoprotein, is a cellular surface antigen characteristically expressed by stem cells. CD34+ stem cells can be further subdivided by the expression of additional surface molecules like CD38 and CD117. In this article we present results from cytogenetic examinations of FACS-isolated stem cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalities; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the receptor for the stem cell factor (also KIT oncogene) as a new cellular surface marker. CD34+/CD117+/- stem cell subpopulations were examined in two patients with AML and three patients with MDS. We found leukemic stem cells in every type of stem cell subpopulation examined (CD34+/CD38-, CD34+/CD38+, CD34+/CD117-, CD34+/CD117+). Secondary, progression-associated chromosome abnormalities likewise were demonstrable in CD34+ cells. In three patients a mosaic of normal and abnormal metaphases was found in the highly purified stem cell subpopulations. We conclude that in AML and MDS stem cells are the target of leukemogenic genetic defects. CD117 as a new marker to isolate different CD34+ subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for autologous stem cell transplantation, high-dose chemotherapy and the pathogenetic concept of leukemogenesis.
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PMID:Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117. 918 Feb 91

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human malignancy. An internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3/ITD) is found in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leukocytosis and a poor prognosis. On the other hand, mutations of the c-KIT gene, which have been found in mast cell leukemia and AML, are clustered in 2 distinct regions, the JM domain and D816 within the activation loop. This study was designed to analyze the mutation of D835 of FLT3, which corresponds to D816 of c-KIT, in a large series of human hematologic malignancies. Several kinds of missense mutations were found in 30 of the 429 (7.0%) AML cases, 1 of the 29 (3.4%) myelodysplastic syndrome (MDS) cases, and 1 of the 36 (2.8%) acute lymphocytic leukemia patients. The D835Y mutation was most frequently found (22 of the 32 D835 mutations), followed by the D835V (5), and D835H (1), D835E (1), and D835N (1) mutations. Of note is that D835 mutations occurred independently of FLT3/ITD. An analysis in the 201 patients newly diagnosed with AML (excluding M3) revealed that, in contrast to the FLT3/ITD mutation (n = 46), D835 mutations (n = 8) were not significantly related to the leukocytosis, but tended to worsen disease-free survival. All D835-mutant FLT3 were constitutively tyrosine-phosphorylated and transformed 32D cells, suggesting these mutations were constitutively active. These results demonstrate that the FLT3 gene is the target most frequently mutated to become constitutively active in AML.
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PMID:Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. 1129 May 75

FLT3 is a receptor tyrosine kinase that may play a role in a significant proportion of leukemias. In addition to being aberrantly expressed in acute leukemias, activating mutations of the FLT3 gene have been found in patients with AML, myelodysplastic syndrome (MDS) and more rarely, ALL. Internal tandem duplications (ITDs) of the FLT3 gene have been detected in 17-34% of patients with AML and portend a poor prognosis for these patients. FLT3 receptors containing ITD mutations (FLT3/ITDs) are constitutively activated in the absence of FLT3 ligand (FL) stimulation leading to the activation of downstream signaling proteins, including ERK and STAT 5. FLT3 activity, therefore, is a logical target for therapeutic intervention. AG1296 is a tyrosine kinase inhibitor of the tyrphostin class that shows inhibitory activity for wild-type FLT3, in addition to the PDGF and c-KIT receptors. We examined the inhibitory effects of AG1296 on FLT3/ITDs isolated from AML patients in the IL-3-dependent cell line, Ba/F3, as well as in primary leukemia samples from AML patients. Immunoprecipitation and immunoblotting analyses demonstrated that FLT3/ITDs were constitutively phosphorylated in the absence of FL. The auto-phosphorylation of FLT3/ITDs was inhibited by AG1296 with an IC(50) of approximately 1 microM. FLT3/ITDs were associated with constitutive phosphorylation of ERK, STAT 5A, STAT 5B, CBL, VAV and SHP2 in Ba/F3 cells. The phosphorylation of these downstream signaling molecules was suppressed in a dose-responsive fashion by AG1296. AG1296 inhibited IL-3 independent growth and induced apoptosis in Ba/F3 cells transformed by FLT3/ITDs. AG1296 also inhibited FLT3 auto-phosphorylation, and induced a cytotoxic effect, in primary AML cells. These findings suggest that inhibiting the activity of FLT3 may have a therapeutic value in some leukemias expressing FLT3/ITDs.
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PMID:Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. 1235 54

Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
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PMID:Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. 1449 2

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.
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PMID:Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. 1468 12

SU11248 is a potent inhibitor of PDGFR, VEGFR, KIT, and Flt3, and is currently under Phase I clinical evaluation as an anticancer drug. A sensitive and specific analytical method for the quantitation of SU11248 and its metabolite in several monkey tissues (liver, kidney, brain and white fat) using LC-MS-MS following semi-automated liquid-liquid extraction (LLE) was developed and validated. Amounts of 50 mg of tissue were homogenized using an ultrasonic processor. After addition of the stable labelled internal standard (IS) and ammonium hydroxide (0.3%), samples were extracted with 2.5 ml of tert-butyl methyl ether. Following centrifugation, aliquots of 1.8 ml of the organic phase were transferred into a 96-well plate. The Packard Multiprobe II robotic liquid handler was used to perform all steps mentioned above. The organic phase was dried and the residue was reconstituted with 800 microl of 15 mM ammonium formate buffer solution (pH 3.25) using a Tomtec Quadra 96 workstation. Aliquots of 10 microl of the resulting solution were injected into the LC-MS-MS system. A Symmetry Shield C8 column (50 mm x 2.1 mm, 3.5 microm) was used to perform the chromatographic analysis. The mobile phase was 15 mM ammonium formate buffer solution (pH 3.25)-acetonitrile (74:26 (v/v)) with a flow-rate of 0.35 ml/min. Retention times of the metabolite and SU11248 were about 2.5 and 3.5 min, respectively. Total cycle time was 5 min. MS detection used the Applied Biosystems-MDS Sciex API 3000 with TurbolonSpray interface and multiple reaction monitoring (MRM) operated in positive ion mode. The method was validated for both compounds over the calibration range of about 2 and 2000 ng/g. The suitability and robustness of the method for in vivo samples were confirmed by analysis of monkey tissues from animals dosed with SU11248.
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PMID:Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. 1475 10

The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.
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PMID:Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. 1597 46

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.
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PMID:Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. 1628 Oct 72

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.
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PMID:Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. 1646 64


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