Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation

Tse, Kam Fai; Mukherjee, Goutam; Small, Donald

doi:10.1038/sj.leu.2401905

Cited by 177 publications

(197 citation statements)

References 63 publications

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“…23,24 Tel is a member of the ETS family of transcriptional factors and is reported to be involved in several chromosomal translocations producing fusion proteins such as Tel-PDGFR in CMML, Tel-ABL in AML and Tel-JAK2 in ALL, all of which result in activated tyrosine kinase domains and cause transformation when expressed in hematopoietic cells. 25 Previously, we developed a model of activated FLT3 receptor by fusing the helix-loop-helix (HLH) domain of Tel to the entire cytoplasmic domain of the FLT3 receptor. 25 This fusion mimics the Tel-PDGFR chromosomal translocation found in a subset of CMML patients with t(5,12).…”

Section: Introductionmentioning

confidence: 99%

“…25 Previously, we developed a model of activated FLT3 receptor by fusing the helix-loop-helix (HLH) domain of Tel to the entire cytoplasmic domain of the FLT3 receptor. 25 This fusion mimics the Tel-PDGFR chromosomal translocation found in a subset of CMML patients with t(5,12). 25,26 Recently, a similar fusion of Tel-FLT3 was observed in a patient with myeloproliferative disorder.…”

Section: Introductionmentioning

confidence: 99%

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Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

et al. 2007

Leukemia

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Evidence is continuing to accumulate that the FMS-like tyrosine kinase 3 (FLT3) receptor plays an important role in acute leukemias. Acute myeloid leukemia patients often express constitutive active mutant forms of the receptor in their leukemic cells. A t(12;13)(p13;q12) translocation between Tel and the FLT3 receptor was recently described in a patient with myeloproliferative disease (MPD). Here a Tel-FLT3 construct mimicking this fusion protein was used to generate transgenic mice. The fusion protein was previously found to constitutively activate FLT3 signaling and transform Ba/F3 cells. Expression of the fusion protein in the transgenic mice was found in all tissues assayed including spleen, bone marrow (BM), thymus and liver. These mice developed splenomegaly and had a high incidence of MPD with extramedullary hematopoiesis in the liver and lymph nodes. Spleens also had increased dendritic and natural killer cell populations. In vitro analysis of the hematopoietic progenitor cells derived from Tel-FLT3 transgenic mice showed a significant increase in the number of CFU-GM in the BM, and CFU-GM, BFU-E and CFU-GEMM in the spleen. BM also showed significant increases of in vivo CFU-S colonies. Thus, transgenic mice expressing constitutively activated Tel-FLT3 develop MPD with a long latency and also result in the expansion of the hematopoietic stem/progenitor cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

et al. 2007

Leukemia

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“…When transduced into primary murine bone marrow progenitor cells, mutant FLT-3 can induce a myeloproliferative disorder. In addition, FLT-3 mutation can transform and confer a leukemogenic potential in the mouse myeloid cells (3,4). Several studies have indicated that the presence of FLT-3 LM or tyrosine kinase domain mutations confer poor prognosis in AML (1,2,5).…”

Section: Introductionmentioning

confidence: 99%

Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3

et al. 2004

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“…FLT-3-ITD initiates the activation of Ras/MAPK and AKT, in a similar manner to the wildtype receptor (11). However, STAT5 also plays a role in FLT-3-ITD signaling (19). Our results show that 100 nmol/L SU11657 reduced phospho-STAT5 in MV4;11 cells to below detectable levels.…”

Section: Discussionmentioning

confidence: 50%

“…Because FLT-3 with an ITD has also been reported to signal through the STAT pathway (19), activation of STAT5 was also examined. No changes in phospho-STAT5 were detected in any of the ALL xenograft lines tested (Fig.…”

Section: Su11657 Inhibits Flt-3 Phosphorylation and Downstream Signalmentioning

confidence: 99%

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

Marković

MacKenzie

Lock

2012

Molecular Cancer Therapeutics

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Human leukemia cells secrete VEGF, which can act in a paracrine manner within the bone marrow microenvironment to promote leukemia cell survival and proliferation. The FLT-3 receptor tyrosine kinase plays an essential role in regulating normal hematopoiesis, but its constitutive activation via mutation in acute leukemias is generally associated with poor outcome. The aim of this study was to investigate interactions between the FLT-3 and VEGF signaling pathways in acute leukemia using cell lines and ex vivo cultures of pediatric acute lymphoblastic leukemia cells following expansion of direct patient explants in immunodeficient mice. Different xenograft lines exhibited variable cell surface FLT-3 expression, as well as basal and FLT-3 ligand-induced VEGF secretion, whereas the MV4;11 cell line, which expresses constitutively active FLT-3, secreted high levels of VEGF. The FLT-3 inhibitor, SU11657, significantly reduced VEGF secretion in three of six xenograft lines and MV4;11 cells, in conjunction with inhibition of FLT-3 tyrosine phosphorylation. Moreover, exposure of xenograft cells to the FLT-3-blocking antibody, D43, also reduced VEGF secretion to basal levels and decreased FLT-3 tyrosine phosphorylation. In terms of downstream signaling, SU11657 and D43 both caused dephosphorylation of extracellular signal-regulated kinase 1/2, with no changes in AKT or STAT5 phosphorylation. Finally, partial knockdown of FLT-3 expression by short interfering RNA also resulted in inhibition of VEGF secretion. These results indicate that FLT-3 signaling plays a central role in the regulation of VEGF secretion and that inhibition of the FLT-3/VEGF pathway may disrupt paracrine signaling between leukemia cells and the bone marrow microenvironment.

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Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation

Cited by 177 publications

References 63 publications

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

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