Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed tandem duplication in the juxtamembrane (JM) domain of the FLT3 (FMS-like tyrosine kinase 3/FLK2, CD135) gene in 94 children with acute myeloid leukemia (AML) and evaluated its correlation with clinical features. Longer polymerase chain reaction (PCR) products were observed in five patients; 1/3 of M0, 119 of M1, 1/39 of M2, 1/9 of M3 and 1/12 of M5. The sequence analyses of abnormal PCR products showed that all the abnormal products were derived from tandem duplications involving the JM domain and that all the lengthened sequences were in-frame as we previously reported. Statistical analyses revealed a significantly lower incidence of the tandem duplication in childhood AML patients than in adult patients (P < 0.05), and significantly shorter disease-free survival in patients with mutant FLT3 than in patients with wild-type FLT3 (P < 0.05). Our results suggest that the tandem duplication in the JM domain of the FLT3 gene is not a frequent phenomenon but might be a factor of poor prognosis in childhood patients with AML.
Leukemia 1999 Jan
PMID:Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. 1004 58

We examined mRNA expression and internal tandem duplication of the Fms-like tyrosine kinase 3 (FLT3) gene in haematological malignancies by reverse transcriptase-polymerase chain reaction (RT-PCR) and genomic PCR followed by sequencing. By RT-PCR, expression of FLT3 was detected in 45/74 (61%) leukaemia cell lines and the frequency of expression of FLT3 was significantly higher in undifferentiated type (B-precursor acute lymphoblastic leukaemia; ALL) than in differentiated type cell lines (B-ALL) (P = 0.0076). Using the genomic PCR method, 194 fresh samples including 87 acute myeloid leukaemias, 60 ALLs, 32 myelodysplastic syndromes (MDSs) and 15 juvenile chronic myelogenous leukaemias (JCMLs) were examined. Tandem duplication was found in 12 (13.8%) AMLs and two (3.3%) ALLs. Sequence analyses of the 14 samples with the duplication revealed that eight showed a simple tandem duplication and six a tandem duplication with insertion. Most of these tandem duplications occurred within exon 11, and two duplications occurred from exon 11 to intron 11 and exon 12. No tandem duplications of FLT3 gene were detected in MDS or JCML. The frequency of tandem duplication of FLT3 gene in childhood AML was lower than that in adult AML so far reported. All of the 12 AML patients with the duplication died within 47 months after diagnosis, whereas two ALL patients with the duplication have survived 44 and 72 months, respectively. These two ALL patients expressed both lymphoid and myeloid antigens and were considered to have biphenotypic leukaemia. These results suggest that tandem duplication is involved in ALL in addition to AML, but not in childhood MDS or JCML, and that childhood AML patients with the tandem duplication have a poor prognosis.
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PMID:Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. 1023 79

The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.
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PMID:Molecular analysis of single colonies reveals a diverse origin of initial clonal proliferation in B-precursor acute lymphoblastic leukemia that can precede the t(12;21) translocation. 1173 41

Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.
Leukemia 2003 Dec
PMID:Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. 1456 19

Constitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBPalpha and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBPalpha was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPalpha in this process.
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PMID:Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. 1459 41

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701-related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease.
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PMID:Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. 1472 87

The role of internal tandem duplication of fms-like tyrosine kinase 3 (FLT3/ITD), mutations at tyrosine kinase domain (FLT3/TKD) and N-ras mutations in the transformation of myelodysplastic syndrome (MDS) to AML was investigated in 82 MDS patients who later progressed to AML; 70 of them had paired marrow samples at diagnosis of MDS and AML available for comparative analysis. Five of the 82 patients had FLT3/ITD at presentation. Of the 70 paired samples, seven patients acquired FLT3/ITD during AML evolution. The incidence of FLT3/ITD at diagnosis of MDS was significantly lower than that at AML transformation (3/70 vs 10/70, P<0.001). FLT3/ITD(+) patients progressed to AML more rapidly than FLT3/ITD(-) patients (2.5+/-0.5 vs 11.9+/-1.5 months, P=0.114). FLT3/ITD(+) patients had a significantly shorter survival than FLT3/ITD(-) patients (5.6+/-1.3 vs 18.0+/-1.7 months, P=0.0008). After AML transformation, FLT3/ITD was also associated with an adverse prognosis. One patient had FLT3/TKD mutation (D835Y) at both MDS and AML stages. Additional three acquired FLT3/TKD (one each with D835 H, D835F and I836S) at AML transformation. Five of the 70 matched samples had N-ras mutation at diagnosis of MDS compared to 15 at AML transformation (P<0.001), one lost and 11 gained N-ras mutations at AML progression. Coexistence of FLT3/TKD and N-ras mutations was found in two AML samples. N-ras mutations had no prognostic impact either at the MDS or AML stage. Our results show that one-third of MDS patients acquire activating mutations of FLT3 or N-ras gene during AML evolution and FLT3/ITD predicts a poor outcome in MDS.
Leukemia 2004 Mar
PMID:Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. 1473 77

Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase (RTK). Between 20% and 30% of acute myeloid leukemia (AML) patients have either an internal tandem duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 receptor leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. The silencing mediator of retinoic and thyroid hormone receptors (SMRT) corepressor mediates transcriptional repression by interacting with transcription factors such as the promyelocytic leukemia zinc finger (PLZF) protein. Previous reports indicate that SMRT interaction with transcription factors can be disrupted by phosphorylation through activation of RTK pathways. We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. Nuclear export was dependent on the SMRT receptor interaction domain (RID), and Flt3-ITD enhances the binding of nuclear-cytoplasm shuttling protein nuclear factor-kappaB-p65 (NFkappaB-p65) to this region. These data suggest that activating mutations of Flt3 may disrupt transcriptional repressor function resulting in aberrant gene regulation and abnormal leukemia cell growth.
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PMID:The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT. 1498 81

FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase, is expressed at high levels in the blasts of approximately 90% of patients with acute myelogenous leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and point mutations in the kinase domain of FLT3 are found in approximately 37% of AML patients and are associated with a poor prognosis. We report here the development and characterization of a fully human anti-FLT3 neutralizing antibody (IMC-EB10) isolated from a human Fab phage display library. IMCEB10 (immunoglobulin G1 [IgG1], kappa) binds with high affinity (KD=158 pM) to soluble FLT3 in enzyme-linked immunosorbent assay (ELISA) and to FLT3 receptor expressed on the surfaces of human leukemia cell lines. IMC-EB10 blocks the binding of FLT3 ligand (FL) to soluble FLT3 in ELISA and competes with FL for binding to cell-surface FLT3 receptor. IMC-EB10 treatment inhibits FL-induced phosphorylation of FLT3 in EOL-1 and EM3 leukemia cells and FL-independent constitutive activation of ITD-mutant FLT3 in BaF3-ITD and MV4;11 cells. Activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and AKT is also inhibited in these cell lines by antibody treatment. The antibody inhibits FL-stimulated proliferation of EOL-1 cells and ligand-independent proliferation of BaF3-ITD cells. In both EOL-1 xenograft and BaF3-ITD leukemia models, treatment with IMC-EB10 significantly prolongs the survival of leukemia-bearing mice. No overt toxicity is observed with IMC-EB10 treatment. Taken together, these data demonstrate that IMC-EB10 is a specific and potent inhibitor of wild-type and ITD-mutant FLT3 and that it deserves further study for targeted therapy of human AML.
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PMID:Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody. 1510 87

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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PMID:Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. 1524 81


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