AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Choudhary, Chunaram; Schwäble, Joachim; Brandts, Christian; Tickenbrock, Lara; Sargin, Bülent; Kindler, Thomas; Fischer, Thomas; Berdel, Wolfgang E.; Müller‐Tidow, Carsten; Serve, Hubert

doi:10.1182/blood-2004-07-2942

Cited by 229 publications

(219 citation statements)

References 52 publications

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“…In murine bone marrow transplantation models as well as in transgenic mice, FLT3-ITD induces a myeloproliferative disease that closely resembles human chronic myelomonocytic leukemia, and FLT3-TKD an oligoclonal lymphoid disorder with longest latency, but neither FLT3-ITD nor FLT3-TDK mutations induce AML. [23][24][25] These findings support the idea that FLT3 alterations are not sufficient to cause AML. Furthermore, the fact that FLT3 mutations can be acquired or lost at relapse or during disease progression is in accordance with the hypothesis that FLT3 mutations are secondary events in leukemogenesis.…”

Section: Flt3supporting

confidence: 73%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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Section: Flt3supporting

confidence: 73%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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“…This is also supported by the finding of clonogenic growth of 32D cells when transfected with FLT3-ITD, but not with wild-type FLT3 or FLT3-D835Y mutation [48]. Given the fact that both receptors are constitutively activated but give rise to different outcomes in terms of signaling and biological phenotype, these observations argue for qualitatively different downstream signaling patterns.…”

Section: Discussionmentioning

confidence: 65%

“…In line with our findings, this indicates signaling differences between ITDs and D835Y of FLT3. As observed in the whole population of AML patients, about 7% of AML patients with FLT3-ITD also carry the D835Y mutation, indicating that the ITD and the D835Y mutant receptors are not functionally redundant [48].…”

Section: Discussionmentioning

confidence: 73%

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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“…FLT3-ITD does while FLT3-TKD does not activate STAT5 and inhibit protein expression of CCAAT/enhancer binding protein␣ and PU.1. 46,47 However, the activation levels of STAT5 and protein expression levels of C/EBP␣ and PU.1 are not affected by RSK2 knockdown in Molm14 cells expressing FLT3-ITD, or in Ba/F3 cells stably expressing FLT3-ITD (data not shown). These results suggest that the RSK2 pathway is involved in FLT3-ITD-induced hematopoietic transformation independent of STAT5, C/EBP␣ and PU.1, which warrants future studies to decipher the signaling mechanism underlying RSK2-mediated lineage-dependent transformation by FLT3-ITD.…”

Section: Flt3-itd Signals Through Rsk2 6891mentioning

confidence: 91%

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

Elf¹,

Blevins²,

Jin³

et al. 2011

Blood

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IntroductionRSK2 is a Ser/Thr kinase that belongs to a family containing 4 members, RSK1 to 4, all of which are downstream substrates of ERK and play a role in various cellular processes including gene expression, cell cycle, survival, and proliferation. RSK family members share both structural and functional similarities, and are uniquely characterized by the presence of 2 distinct kinase domains, both of which are catalytically functional 1-3 (reviewed in Blenis, 4 Frodin and Gammeltoft, 5 and Anjum and Blenis 6 ). The carboxyl-terminal kinase (CTK) domain is responsible for autophosphorylation at Ser386 (numbering based on the murine RSK2 amino acid sequence), which is critical for RSK activation, while the N-terminal kinase (NTK) domain phosphorylates RSK substrates. 2 We recently reported that tyrosine phosphorylation of RSK2 facilitates inactive ERK binding to RSK2 in the initial activation step, and disrupts an autoinhibitory region of RSK2 to achieve full activation. [7][8][9] RSK2 phosphorylates multiple signaling effectors that possess RRXS/T or RXRXXS/T motifs. 10 These RSK2 phosphorylation targets include transcriptional regulators such as cAMP-response element-binding protein (CREB), 11 c-Fos, 12,13 NFATc4, 14 NFAT3, 15 ATF4, 16 and Nur77. 17 Phosphorylation and activation of these transcription factors are important for regulation of gene expression. RSK2 also phosphorylates histone H3, which contributes to chromatin remodeling during mitosis and transcriptional activation. 18 In addition, RSK2 promotes cell survival by phosphorylating and inhibiting proapoptotic protein factors including BAD,19 Bim, 20 and death-associated protein kinase (DAPK). 21 Moreover, RSK2 promotes proliferation by phosphorylating GSK3␤, 22 NHE-1, 23 and p27 kip1 . 24 Therefore, RSK2 may serve as a key regulator by activating multiple signaling effectors in a signaling network that promotes cell survival and proliferation.Defects in the human RSK2 gene are associated with CoffinLowry syndrome (CLS), an X-linked mental retardation. 25,26 Although there is no evidence that RSK2 is mutated in human cancers, RSK2 signaling has been demonstrated to play a key role in the pathogenesis and disease progression of some human malignancies, including metastatic head and neck cancer, 27 FGFR1-expressing prostate cancer, 28,29 and osteosarcoma. 16,30 We recently found that oncogenic FGFR3 phosphorylates and activates RSK2 to induce hematopoietic transformation. 7,9 Targeting RSK2 but not RSK1 by siRNA or treatment with a specific RSK inhibitor fmk 31,32 effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells and primary patient myeloma cells. These findings suggest a critical role for RSK2 in FGFR3-induced hematopoietic transformation.In this report, we focus on the role of RSK2 in other hematopoietic malignancies induced by different leukemogenic tyrosine kinases (LTKs) including BCR-ABL and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutant. BCR-ABL is a constitutively active fus...

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AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Cited by 229 publications

References 52 publications

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

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