FLT3 mutations in acute myeloid leukemia cell lines

Quentmeier, Hilmar; Reinhardt, Julia; Zaborski, Margarete; Drexler, Hans G.

doi:10.1038/sj.leu.2402740

Cited by 246 publications

(211 citation statements)

References 23 publications

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“…and FL simultaneously, which indicates a potential role for the ligand even when the receptor is constitutively activated [39]. In a study by Zheng et al primary AML blasts were screened for FLT3 and FL protein co-expression, suggesting autocrine or paracrine stimulatory loops [40] and further supporting our results.…”

Section: Discussionsupporting

confidence: 86%

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Razumovskaya¹,

Masson²,

Khan

et al. 2009

Experimental Hematology

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Objective. Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia c due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants.Methods. We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the use of a panel of phosphospecific antibodies directed against potential tyrosine phosphorylation sites in FLT3, we identified several novel phosphorylation sites in FLT3 and studied the kinetics and specificity of ligand-induced phosphorylation in living cells.Results. Eight phosphorylated tyrosines (pY589, pY591, pY599, pY726, pY768, pY793, pY842 and pY955) were investigated and shown to be differentially phosphorylated in the wild-type versus the mutated receptors. Furthermore, we show that tyrosines 726, 793 and 842 are novel phosphorylation sites of FLT3 in intact cells. Conclusion.In this study, we have looked at the site-specific phosphorylation in the wild-type FLT3 in comparison to the mutants found in AML. We observed not only quantitative changes but more importantly, qualitative differences in the phosphorylation patterns of the wild-type and the mutated FLT3 receptors, which might contribute to the understanding of the mechanisms by which FLT3 contributes to AML in patients with mutations in FLT3.

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Section: Discussionsupporting

confidence: 86%

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Razumovskaya¹,

Masson²,

Khan

et al. 2009

Experimental Hematology

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“…It has been shown that MOLM13 and MV4-11 cell lines carry FLT3-ITD (internal tandem duplication), whereas FLT3 is in wild-type configuration in THP-1 and U937 cell lines (Quentmeier et al, 2003). THP-1 cells express a large amount of FLT3 but U937 cells do not express FLT3 (Yao et al, 2003).…”

Section: Effects Of Pkc412 On Growth Kinetics Of Aml Cell Lines With mentioning

confidence: 99%

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G 2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G 2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutationdependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia.

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“…17 THP-1 is a human acute monocytic leukemia cell line expressing wild-type FLT3. TF-1 is a human erythroleukemia cell line that does not express FLT3.…”

Section: Cell Linesmentioning

confidence: 99%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. 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.

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FLT3 mutations in acute myeloid leukemia cell lines

Cited by 246 publications

References 23 publications

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

FES kinases are required for oncogenic FLT3 signaling

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