Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FLT3 is a class III receptor tyrosine kinase together with KIT, FMS and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence, and subsequently as a missense mutation of D835 (FLT3/KDM) within a kinase domain. Furthermore, point mutations, deletions, and insertions in the codons surrounding D835 have also been found. FLT3/ITD and FLT3/KDM occur in 15% to 35% and 5% to 10%, respectively, of patients with AML. FLT3 mutations are, therefore, the most frequent genetic alterations so far reported in AML. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. Although the clinical significance of FLT3/KDM is controversial, the meta-analysis suggests its adverse effect on the outcome. FLT3/ITD is far less common in patients with ALL, whereas FLT3/KDM is recurrently found in patients with ALL, especially in those harboring an MLL gene rearrangement or hyperdiploidy. The overexpression of FLT3 transcripts has been demonstrated in a pro-portion of the AML patients without FLT3 mutations, which are associated with a poor prognosis for overall survival. Routine screening of FLT3 mutations is recommended to stratify the patients into distinct risk groups, while the optimal treatment strategy for patients with FLT3 mutations should be further evaluated.
 ...
PMID:Clinical significance of FLT3 in leukemia. 1614 37

Myeloid malignancies are clonal disorders that are characterized by acquired somatic mutation in hematopoietic progenitors. Recent advances in our understanding of the genetic basis of myeloid malignancies have provided important insights into the pathogenesis of acute myeloid leukemia (AML) and myeloproliferative diseases (MPD) and have led to the development of novel therapeutic approaches. In this review, we describe our current state of understanding of the genetic basis of AML and MPD, with a specific focus on pathogenetic and therapeutic significance. Specific examples discussed include RAS mutations, KIT mutations, FLT3 mutations, and core binding factor rearrangements in AML, and JAK2 mutations in polycythemia vera, essential thrombocytosis, and chronic idiopathic myelofibrosis.
 ...
PMID:Genetics of myeloid malignancies: pathogenetic and clinical implications. 1657 17

Heat shock protein 90 (Hsp90) serves as a chaperone for a number of cell signaling proteins, including many tyrosine and serine/threonine kinases, which are involved in proliferation and/or survival. The benzoquinone ansamycin geldanamycin has been shown to bind to Hsp90 and to specifically inhibit this chaperone's function, resulting in client protein destabilization. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a chemical derivative of geldanamycin. KIT is the receptor for stem cell factor (SCF) and required for normal hematopoiesis. Mutations in c-Kit result in ligand-independent tyrosine kinase activity and uncontrolled cell proliferation. Kasumi-1 is t(8;21) acute myeloid leukemia (AML) cell line harboring mutated KIT with Asn822Lys substitution. Our present studies demonstrate that 17-AAG inhibits Kasumi-1 cells proliferation and exerts apoptosis- and differentiation-inducing effects in a dose- and time-dependent manner. The growth-inhibitory IC50 value for 17-AAG treatment is 0.62mumol/L. Characteristic apoptotic features were confirmed by morphology, internucleosomal DNA fragmentation, and annexin V staining. 17-AAG also causes the G0/G1 block of Kasumi-1 cells. Significantly, 17-AAG-induced apoptosis of Kasumi-1 cells is associated with a decline in KIT protein level. Our findings strongly suggest that 17-AAG might be an effective therapeutic agent targeting AML cells harboring mutated KIT.
 ...
PMID:The Hsp90 inhibitor 17-allylamide-17-demethoxygeldanamycin induces apoptosis and differentiation of Kasumi-1 harboring the Asn822Lys KIT mutation and down-regulates KIT protein level. 1621 82

Mutations in codon D816 of the KIT gene represent a recurrent genetic alteration in acute myeloid leukemia (AML). To clarify the biologic implication of activation loop mutations of the KIT gene, 1940 randomly selected AML patients were analyzed. In total, 33 (1.7%) of 1940 patients were positive for D816 mutations. Of these 33 patients, 8 (24.2%) had a t(8;21), which was significantly higher compared with the subgroup without D816 mutations. Analyses of genetic subgroups showed that KIT-D816 mutations were associated with t(8;21)/AML1-ETO and other rare AML1 translocations. In contrast, other activating mutations like FLT3 and NRAS mutations were very rarely detected in AML1-rearranged leukemia. KIT mutations had an independent negative impact on overall (median 304 vs 1836 days; P = .006) and event-free survival (median 244 vs 744 days; P = .003) in patients with t(8;21) but not in patients with a normal karyotype. The KIT-D816V receptor expressed in Ba/F3 cells was resistant to growth inhibition by the selective PTK inhibitors imatinib and SU5614 but fully sensitive to PKC412. Our findings clearly indicate that activating mutations of receptor tyrosine kinases are associated with distinct genetic subtypes in AML. The KIT-D816 mutations confer a poor prognosis to AML1-ETO-positive AML and should therefore be included in the diagnostic workup. Patients with KIT-D816-positive/AML1-ETO-positive AML might benefit from early intensification of treatment or combination of conventional chemotherapy with KIT PTK inhibitors.
 ...
PMID:KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. 1625 34

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.
 ...
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

Haploinsufficiency of RUNX1/AML1 is associated with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML), but the causal relationship remains to be addressed experimentally. Mice heterozygous for the Runx1 null mutation, Runx1+/-, are considered to be genetically comparable with human FPD/AML patients but do not develop spontaneous leukaemia. To induce additional genetic alterations, retroviral insertional mutagenesis was employed with the use of BXH2 mice, which develop myeloid leukaemia because of the random integration of retrovirus present in the mouse. Heterozygous disruption of Runx1 in BXH2 mice resulted in a shortening of the latency period of leukaemia. In addition, BXH2-Runx1+/- mice exhibited more marked myeloid features than control mice. Moreover, the c-Kit gene, mutated in human RUNX leukaemias, was recurrently activated in BXH2-Runx1+/- mice, and a colony-forming assay revealed synergism between the Runx1+/- status and c-KIT overexpression. In conclusion, the BXH2-Runx1+/- system is a promising mouse model to investigate the mechanism of leukaemogenesis in FPD/AML.
 ...
PMID:Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. 1628 42

Patients with t(8;21) acute myeloid leukemia (AML) are considered to have a good prognosis; however, approximately 50% of them relapse. The genetic alterations associated with a poor outcome in t(8;21) AML remain unknown. Recently, aberrations of receptor tyrosine kinases (RTKs) were frequently found in patients with AML. However, the prevalence and prognostic impact of RTK aberrations in pediatric t(8;21) AML remains undetermined. Here, we found the kinase domain mutations of the KIT gene in 8 (17.4%) of 46 patients with t(8;21) AML among newly diagnosed pediatric patients with AML treated on the AML99 protocol in Japan. Significant differences between patients with or without KIT mutations were observed in the 4-year overall survival (50.0% versus 97.4%, P = .001), disease-free survival (37.5% versus 94.7%, P < .001) and relapse rate (47.0% versus 2.7%, P < .001). Furthermore, FLT3 internal tandem duplication was found in only 2 (4.3%) patients. These results suggested that KIT mutations are strongly associated with a poor prognosis in pediatric t(8;21) AML.
 ...
PMID:KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. 1629 92

The detailed characterization of genetic and molecular aberrations in acute myeloid leukemia (AML) has substantially improved our understanding of the pathogenesis of this disease. With an incidence of up to 12% in all AML cases, the translocation t(8;21), forming the AML1-ETO fusion gene, is one of the most common genetic aberrations in AML. Experimental data have shown that AML1-ETO is not sufficient to induce leukemia by itself, but has to collaborate with other genetic alterations for leukemic transformation. These data are supported by observations in AML patients, who recurrently show activating mutations of the receptor tyrosine kinase FLT3 or c-KIT together with the AML1-ETO fusion gene. These findings might have clinical implications and provide a rationale to test RTK inhibitors in the treatment of patients with core binding factor AML and concurrent activating RTK mutations.
 ...
PMID:AML1-ETO needs a partner: new insights into the pathogenesis of t(8;21) leukemia. 1629 39

The prognosis for younger adults (< or = 55-60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%-80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%-40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%-55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation.Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPalpha, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.
 ...
PMID:New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. 1630 72

Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD(816)) was associated with a high white blood cell count at diagnosis (median, 29.60 x 10(9)/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD(816) mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT(-)) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD(816) (n = 7) and the c-KIT(-) patients. These findings indicate that c-KIT TKD(816) mutation has a negative impact on the outcome of AML with t(8;21).
 ...
PMID:Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. 1638 25


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