Genomes and Genes
fms like tyrosine kinase 3
Summary: A receptor tyrosine kinase that is involved in HEMATOPOIESIS. It is closely related to FMS PROTO-ONCOGENE PROTEIN and is commonly mutated in acute MYELOID LEUKEMIA.
- Sanz M, Burnett A, Lo Coco F, Lowenberg B. FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Curr Opin Oncol. 2009;21:594-600 pubmed publisher..These agents are also being tested in combination with conventional chemotherapy. Oral FLT3 inhibitors offer a hope of improved treatment outcomes for patients with relapsed and newly diagnosed AML. ..
- Langer C, Marcucci G, Holland K, Radmacher M, Maharry K, Paschka P, et al. Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2009;27:3198-204 pubmed publisher..CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets. ..
- Burnett A, Hills R, Green C, Jenkinson S, Koo K, Patel Y, et al. The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, . Blood. 2010;115:948-56 pubmed publisher..ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy. ..
- Koh Y, Park J, Ahn K, Kim I, Bang S, Lee J, et al. Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway. Ann Hematol. 2009;88:1089-97 pubmed publisher..FLT3-ITD is a predictive and prognostic marker only in monocyte lineage patients. This result suggests an existence of distinct subset of monocyte lineage AML with leukemogenesis involving FLT3 activating pathway. ..
- Wang S, Jabbar K, Lu G, Chen S, Galili N, Vega F, et al. Trisomy 11 in myelodysplastic syndromes defines a unique group of disease with aggressive clinicopathologic features. Leukemia. 2010;24:740-7 pubmed publisher..97). We conclude that trisomy 11 in MDS correlates with clinical aggressiveness, may suggest an early/evolving AML with myelodysplasia-related changes and is best considered a high-risk cytogenetic abnormality in MDS prognostication. ..
- Small D. Targeting FLT3 for the treatment of leukemia. Semin Hematol. 2008;45:S17-21 pubmed publisher..Anti-FLT3 antibodies may also prove to be an excellent way of targeting FLT3 in AML and acute lymphocytic leukemia (ALL) by inhibiting signaling and through antibody-dependent cell-mediated cytotoxicity. ..
- Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prebet T, et al. FES kinases are required for oncogenic FLT3 signaling. Leukemia. 2010;24:721-8 pubmed publisher..FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD. ..
- Stölzel F, Steudel C, Oelschlagel U, Mohr B, Koch S, Ehninger G, et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol. 2010;89:653-62 pubmed publisher..In summary, resistance against PKC412 appears to be mediated by up-regulation of anti-apoptotic genes and down-regulation of proapoptotic signals as well as genes that are involved in normal and malignant hematopoiesis. ..
- O Keeffe M, Fancke B, Hochrein H. The generation of plasmacytoid and conventional dendritic cells with M-CSF. Methods Mol Biol. 2010;595:187-93 pubmed publisher..The M-CSF-driven DC (MDC) developed independently of FL and resembled the DC types present in the spleen in the steady state. ..
- Muranyi A, Dedhar S, Hogge D. Targeting integrin linked kinase and FMS-like tyrosine kinase-3 is cytotoxic to acute myeloid leukemia stem cells but spares normal progenitors. Leuk Res. 2010;34:1358-65 pubmed publisher..In contrast, little toxicity toward normal bone marrow progenitors was observed, demonstrating that candidate leukemic stem cells can be eliminated by inhibition of these targets while normal hematopoietic counterparts are spared. ..
- Hochweller K, Miloud T, Striegler J, Naik S, Hämmerling G, Garbi N. Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loop. Blood. 2009;114:4411-21 pubmed publisher..This mechanism is different to those known for other immune cell types, such as the B- and T-cell compartments, whereby lymphopenia induces proliferation of already differentiated lymphocytes. ..
- Tobon G, Renaudineau Y, Hillion S, Cornec D, Devauchelle Pensec V, Youinou P, et al. The Fms-like tyrosine kinase 3 ligand, a mediator of B cell survival, is also a marker of lymphoma in primary Sjögren's syndrome. Arthritis Rheum. 2010;62:3447-56 pubmed publisher..Flt-3 is mainly expressed by Bm2 and Bm2? cells. Serum levels of Flt-3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy. ..
- Gentles A, Plevritis S, Majeti R, Alizadeh A. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010;304:2706-15 pubmed publisher..07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005). High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML. ..
- Gaidzik V, Schlenk R, Moschny S, Becker A, Bullinger L, Corbacioglu A, et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood. 2009;113:4505-11 pubmed publisher..In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1(mut)/FLT3-ITD(pos). ..
- Oelschlaegel U, Mohr B, Schaich M, Schäkel U, Kroschinsky F, Illmer T, et al. HLA-DRneg patients without acute promyelocytic leukemia show distinct immunophenotypic, genetic, molecular, and cytomorphologic characteristics compared to acute promyelocytic leukemia. Cytometry B Clin Cytom. 2009;76:321-7 pubmed publisher..The results of the present study show that an immunophenotypic, molecular, and cytomorphologic separation of both HLA-DR(neg) leukemia subgroups is possible indicating that both groups are biologically distinct. ..
- Masson K, Liu T, Khan R, Sun J, Ronnstrand L. A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival. Br J Haematol. 2009;146:193-202 pubmed publisher..These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions. ..
- Ricklin Gutzwiller M, Moulin H, Zurbriggen A, Roosje P, Summerfield A. Comparative analysis of canine monocyte- and bone-marrow-derived dendritic cells. Vet Res. 2010;41:40 pubmed publisher..Taken together, our results are the basis for further characterization of canine DC subsets with respect to their role in inflammation and immune responses. ..
- Breitenbuecher F, Markova B, Kasper S, Carius B, Stauder T, Bohmer F, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113:4063-73 pubmed publisher..The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs. ..
- Tsuruyama T, Imai Y, Takeuchi H, Hiratsuka T, Maruyama Y, Kanaya K, et al. Dual retrovirus integration tagging: identification of new signaling molecules Fiz1 and Hipk2 that are involved in the IL-7 signaling pathway in B lymphoblastic lymphomas. J Leukoc Biol. 2010;88:107-16 pubmed publisher..Identification of the dual MLV integration sites in B-LBLs, therefore, will provide an excellent tool for identification of the signaling pathways in B-LBLs. ..
- Dufour A, Schneider F, Metzeler K, Hoster E, Schneider S, Zellmeier E, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28:570-7 pubmed publisher..These findings are of great significance for risk-adapted therapeutic strategies in AML. ..
- Bodo J, Durkin L, Hsi E. Quantitative in situ detection of phosphoproteins in fixed tissues using quantum dot technology. J Histochem Cytochem. 2009;57:701-8 pubmed publisher..QD immunofluorescence is an ideal method for in situ quantitation of PPs in fixed samples, providing valuable cell type-specific and subcellular information about pathway activation in primary tissues. ..
- Naik S. Generation of large numbers of pro-DCs and pre-DCs in vitro. Methods Mol Biol. 2010;595:177-86 pubmed publisher..As these precursors are largely DC-restricted, they can be used to either reconstitute a mouse with DCs of desired background, to study the developmental steps in vitro or in vivo, among other purposes. ..
- Seedhouse C, Grundy M, Shang S, Ronan J, Pimblett H, Russell N, et al. Impaired S-phase arrest in acute myeloid leukemia cells with a FLT3 internal tandem duplication treated with clofarabine. Clin Cancer Res. 2009;15:7291-8 pubmed publisher..Efficient DNA repair may render the cells resistant to a short pulse of the drug, but a failure of cell cycle checkpoint(s) in S phase renders the cells sensitive to prolonged exposure. ..
- Zeng Z, Shi Y, Samudio I, Wang R, Ling X, Frolova O, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009;113:6215-24 pubmed publisher..Disruption of these interactions with CXCR4 inhibitors represents a novel strategy of sensitizing leukemic cells by targeting their protective bone marrow microenvironment. ..
- Yoshimoto G, Miyamoto T, Jabbarzadeh Tabrizi S, Iino T, Rocnik J, Kikushige Y, et al. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009;114:5034-43 pubmed publisher..This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling. ..
- Gregory T, Wald D, Chen Y, Vermaat J, Xiong Y, Tse W. Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. J Hematol Oncol. 2009;2:23 pubmed publisher..Further prospective studies are needed to confirm if poorer risk NC-AML patients have improved clinical outcomes after more aggressive therapy. ..
- Chen W, Konoplev S, Medeiros L, Koeppen H, Leventaki V, Vadhan Raj S, et al. Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer. 2009;115:5481-9 pubmed publisher..Recognition of the distinctive morphologic features of AML with cuplike nuclei may be helpful in streamlining the workup of these neoplasms. ..
- Zaker F, Mohammadzadeh M, Mohammadi M. Detection of KIT and FLT3 mutations in acute myeloid leukemia with different subtypes. Arch Iran Med. 2010;13:21-5 pubmed..The presence of fms-like tyrosine kinase 3 was significantly associated with M3 morphology and mutations of KIT were significantly associated with M2 and M4 subtypes. ..
- Barbarroja N, Torres L, Rodriguez Ariza A, Valverde Estepa A, Lopez Sanchez L, Ruiz Limon P, et al. AEE788 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with antiproliferative and proapoptotic effects in acute myeloid leukemia. Exp Hematol. 2010;38:641-52 pubmed publisher..Taken together, the activity of AEE788 might represent a promising new option of targeting FLT3 for the treatment of AML. ..
- Ho P, Alonzo T, Kopecky K, Miller K, Kuhn J, Zeng R, et al. Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia. 2010;24:909-13 pubmed publisher..Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML. ..
- Eriksson A, Höglund M, Lindhagen E, Aleskog A, Hassan S, Ekholm C, et al. Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia. Biochem Pharmacol. 2010;80:1507-16 pubmed publisher..Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML. ..
- Braoudaki M, Karpusas M, Katsibardi K, Papathanassiou C, Karamolegou K, Tzortzatou Stathopoulou F. Frequency of FLT3 mutations in childhood acute lymphoblastic leukemia. Med Oncol. 2009;26:460-2 pubmed publisher..This is in accordance to previous studies indicating a higher incidence in the patient subgroup associated with hyperdiploidy. ..
- Youssoufian H, Rowinsky E, Tonra J, Li Y. Targeting FMS-related tyrosine kinase receptor 3 with the human immunoglobulin G1 monoclonal antibody IMC-EB10. Cancer. 2010;116:1013-7 pubmed publisher..Future clinical trials will test these notions formally and will identify the most appropriate opportunities for this member of a new generation of antileukemic therapies. ..
- Perugini M, Kok C, Brown A, Wilkinson C, Salerno D, Young S, et al. Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation. Leukemia. 2009;23:729-38 pubmed publisher..Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML. ..
- Kuo M, Liang D, Huang C, Shih Y, Wu J, Lin T, et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia. 2009;23:1426-31 pubmed publisher..3 months in those without mutations (P=0.022). This study showed for the first time a high frequency of RUNX1 mutations in CMML. C-terminal mutations might be associated with a more frequent and rapid AML transformation. ..
- Onai N, Manz M, Schmid M. Isolation of common dendritic cell progenitors (CDP) from mouse bone marrow. Methods Mol Biol. 2010;595:195-203 pubmed publisher..Thus, these results prove the existence of a common developmental pathway for at least some pDCs and cDCs in lymphoid organs in vivo. ..
- Kumar R, Crouthamel M, Rominger D, Gontarek R, Tummino P, Levin R, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer. 2009;101:1717-23 pubmed publisher..Activity against c-kit and Flt-3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients. ..
- Kenins L, Gill J, Hollander G, Wodnar Filipowicz A. Flt3 ligand-receptor interaction is important for maintenance of early thymic progenitor numbers in steady-state thymopoiesis. Eur J Immunol. 2010;40:81-90 pubmed publisher..Together, these results show that FL expression by thymic stromal fibroblasts interacting with Flt3+ T-cell progenitors is important for the physiological maintenance of early T-cell development. ..
- Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009;114:1607-17 pubmed publisher..Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations. ..
- Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K, et al. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia. Eur J Haematol. 2009;83:90-8 pubmed publisher..These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation. ..
- Jaiswal S, Jamieson C, Pang W, Park C, Chao M, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138:271-85 pubmed publisher..We conclude that CD47 upregulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing. ..
- Rathinam C, Thien C, Flavell R, Langdon W. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell. 2010;18:341-52 pubmed publisher..The characterization of these perturbations provides direction for therapeutics that may aid the treatment of patients with c-Cbl mutations...
- Curtin J, King G, Barcia C, Liu C, Hubert F, Guillonneau C, et al. Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain. J Immunol. 2006;176:3566-77 pubmed