Constitutive Fms‐like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells

Kim, Kyu Tae; Baird, Kristin; Davis, Sean; Piloto, Obdulio; Levis, Mark J.; Li, Li; Chen, Peili; Meltzer, Paul S.; Small, Donald

doi:10.1111/j.1365-2141.2007.06696.x

Cited by 35 publications

(41 citation statements)

References 41 publications

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“…We were motivated to investigate cdc25A because its expression is driven by c-myc (32), which is known to be aberrantly upregulated in FLT3-ITD cells (33). However, this might not be the relevant pathway: it is also of note that Pim-1, another major transcriptional target of FLT3-ITDs (34), is reported to activate cdc25A (35), although the mechanism is unclear (36).…”

Section: Discussionmentioning

confidence: 99%

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Seedhouse

Grundy²,

Shang³

et al. 2009

Clinical Cancer Research

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Purpose: Acute myeloid leukemia cells with an internal tandem duplication mutation of FLT3 (FLT3-ITD) have effective DNA repair mechanisms on exposure to drugs. Despite this, the phenotype is not associated with primary resistant disease. We show defects in the response of mutant FLT3 AML cells to the S-phase drug clofarabine that could account for the apparent contradiction. Experimental Design: We studied responses of AML cells to clofarabine in vitro. Results: When treated with a short pulse of clofarabine, FLT3-ITD-harboring MOLM-13 and MV4.11 cells undergo similar damage levels (γH2AX foci) to wild-type cells but have a better repair capability than wild-type cells. However, whereas the wild-type cells undergo rapid S-phase arrest, the S-phase checkpoint fails in mutant cells. Cell cycle arrest in response to DNA damage in S phase is effected via loss of the transcriptional regulator cdc25A. This loss is reduced or absent in clofarabine-treated FLT3 mutant cells. Furthermore, cdc25A message levels are maintained by the FLT3-ITD, such that message is reduced by 87.5% on exposure to FLT3 small interfering RNA. Primary FLT3-ITD samples from untreated patients also display impaired cell cycle arrest and show enhanced sensitivity on prolonged treatment with clofarabine compared with wild-type samples. Clofarabine is a second-generation purine nucleoside analogue with favorable pharmacologic properties (resistance to deaminase degradation and stability in gastric acid) and is in increasing clinical use for the treatment of AML (5-9). Because of the potential oral availability and its acceptable toxicity with respect to mucositis and alopecia, its use has recently been explored in older AML patients with promising results. 3Mechanisms supporting heterogeneity in sensitivity and resistance to clofarabine have been reported in the literature; particularly, a variability in the cellular accumulation of clofarabine triphosphate in circulating blasts has been recorded (6, 7). We have previously shown efficient DNA repair following anthracycline exposure in AML cells with a FLT3-ITD (10) and were thus initially interested to discover whether DNA damage and repair mechanisms are important in the response of FLT3-ITD cells to clofarabine. There is a well-characterized assay (the measurement of γH2AX) that can be used as a biomarker of the effectiveness of clofarabine at reaching its DNA target and inducing a damage response (7,11). The use of this assay has enabled us to focus on events subsequent to clofarabine-induced DNA damage and to dissect mechanisms by which cells proceed to apoptosis or recovery subsequent to the initial damage response signals.The damage response pathway is closely linked to cell cycle arrest mechanisms. In a well-documented but fast-evolving model of cell cycle arrest in S phase (the phase in which 3 A.K. Burnett et al

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Section: Discussionmentioning

confidence: 99%

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Seedhouse

Grundy²,

Shang³

et al. 2009

Clinical Cancer Research

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“…9,10 The biologic consequences are enhanced proliferation and reduced apoptosis of the myeloblasts, which contribute to leukemogenesis. [11][12][13][14][15] Patients with FLT3-ITD respond poorly to conventional chemotherapy and have an inferior prognosis, 16,17 particularly in those with a high FLT3-ITD ϩ cell burden, 18 long ITD sequences, 19 and multiple FLT3-ITD ϩ subclones, 20 underscoring a pathogenetic role of FLT3-ITD in human AML. In mice, knock-in of a heterozygous FLT3-ITD resulted in a preleukemic model of a myeloproliferative disease, providing an in vivo demonstration of the important role of FLT3 in leukemia initiation.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

Man¹,

Fung²,

Ho³

et al. 2012

Blood

256

244

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IntroductionAcute myeloid leukemia (AML) refers to a genetically and biologically heterogeneous group of diseases characterized by an abnormal increase of myeloblasts in the bone marrow (BM) and peripheral blood (PB) circulation. Chemotherapy and hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment, but these modalities have reached an impasse with an overall cure rate of only 30%-40%. 1 An attractive strategy is to target specific genetic and biochemical alterations in AML, thereby providing an alternative treatment modality that may improve patient outcome. 2,3 FLT3 (fms-like tyrosine kinase-3) is a receptor tyrosine kinase (RTK) that is highly expressed in hematopoietic stem and progenitor cells. It includes an extracellular domain (ECD), a transmembrane domain (TMD), a juxtamembrane domain (JMD), and 2 tyrosine kinase domains (TKDs) separated by a kinase insert. 4 On binding with FLT3 ligand secreted by BM stromal cells, FLT3 undergoes dimerization, phosphorylation, and TKD activation. The FLT3 gene is mutated in approximately 30% of AMLs, particularly those with normal karyotypes, t(6;9), t(15;17), or trisomy 8. 5,6 The most common mutation is an internal tandem duplication (ITD) up to a few hundred base-pairs within the JMD. Single-base mutations have also been described, most commonly resulting in a substitution of aspartic acid with tyrosine or less commonly a histidine at residue 835 in the TKD. 7,8 At a molecular level, these mutations result in constitutive activation of the FLT3 receptor and hence downstream PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK/ STAT pathways. 9,10 The biologic consequences are enhanced proliferation and reduced apoptosis of the myeloblasts, which contribute to leukemogenesis. [11][12][13][14][15] Patients with FLT3-ITD respond poorly to conventional chemotherapy and have an inferior prognosis, 16,17 particularly in those with a high FLT3-ITD ϩ cell burden, 18 long ITD sequences, 19 and multiple FLT3-ITD ϩ subclones, 20 underscoring a pathogenetic role of FLT3-ITD in human AML. In mice, knock-in of a heterozygous FLT3-ITD resulted in a preleukemic model of a myeloproliferative disease, providing an in vivo demonstration of the important role of FLT3 in leukemia initiation. 21 We 22 and others 23,24 have shown that the FLT3-ITD allele can be found in leukemia initiating cells (LICs), as distinguished by their capability of regenerating leukemic progeny in transplanted immunodeficient mice. Therefore, targeting FLT3-ITD might provide a novel approach to therapeutic intervention.Several clinical trials on multi-TK inhibitors with different FLT3 specificities and in vitro efficacies have been reported, including the use of midostaurin, 25 lestautinib, 26 tandutinib, 27 sunitinib, 28 and sorafenib. 29 In most studies, clinical efficacy was restricted to FLT3-ITD ϩ AML and correlated with inactivation of FLT3 phosphorylation. 25,[30][31][32] Complete remission was rare and limited to anecdotal reports in relapsed AML after allogeneic HSCT. 33 Furthermore, after ...

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“…[3][4][5][6] In AML, this is driven at least in part by activation of receptor tyrosine kinases such as the Flt3-internal tandem duplication (Flt3-ITD) mutation 5,7,8 found in approximately one third of AML patients. The JAK/STAT pathway, a key mediator of cytokine and growth factor signaling, plays an important role in regulating Pim expression.…”

Section: Introductionmentioning

confidence: 99%

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Keeton

McEachern

Dillman

et al. 2014

Blood

220

216

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Constitutive Fms‐like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells

Cited by 35 publications

References 41 publications

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

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