Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells

Towatari, Masayuki; Iida, Hiroatsu; Tanimoto, Mitsune; Iwata, Hiroji; Hamaguchi, Michinari; Saito, Hidehiko

doi:10.1038/sj.leu.2400617

Cited by 139 publications

(118 citation statements)

References 6 publications

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“…As shown in Figure 2a, mutant Flt3 was phosphorylated independent of ligand, while wild-type Flt3 was phosphorylated with ligand stimulation only. Activation (phosphorylation) of MAP kinase (ERK1 and ERK2) was examined with the mobility shift of the phosphorylated form of MAP kinase by low-bis SDS ± PAGE followed by Western blot analysis (Towatari et al, 1997). In mut Flt3 ± BAF3, constitutive phosphorylation of both ERK1 and ERK2 was observed without ligand stimulation (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

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Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

et al. 2000

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Section: Resultsmentioning

confidence: 99%

“…Mobility shift analysis to dissect the phosphorylated forms of ERK1/ERK2 from the unphosphorylated forms was conducted as described previously (Towatari et al, 1997). Equivalent amounts of protein were immunoprecipitated with anti-Flt3, anti-Lyn, or PY20 antibodies.…”

Section: Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

et al. 2000

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“…[14][15][16][17][18][19] Specifically, internal tandem Table 2 Common adverse events by dose cohort duplication mutation of FLT3, producing a constitutively activated receptor tyrosine kinase, has been associated with adverse prognosis. [16][17][18] C-kit mutations can adversely affect prognosis in patients with core-binding factor leukemias.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

et al. 2010

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Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m 2 ), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m 2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m 2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C max and area under the curve (AUC) from 8 to 32 mg/m 2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twiceweekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m 2 .

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“…49,51 In agreement with increased MAP kinase activity correlating with increased transformation and proliferation, elevated basal levels of MAP kinase activity are frequently found in acute myelogenous leukemia cells. 52 However, more defined studies examining the extent and duration of MAP kinase activation, are now beginning to show that a simplistic view of increased activation of MAP kinase equating with increased proliferation is not necessarily valid.…”

Section: An Overview For the Role Of The Map Kinase Pathway In Prolifmentioning

confidence: 99%

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

et al. 1998

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During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21 Cip-1/MDA6/WAF1 . These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio-and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21 Cip-1/MDA6/WAF1 expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.

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Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells

Abstract: of the signal but also as so-called oncogenes. In the light of

Cited by 139 publications

References 6 publications

Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

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