Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo

Arreba-Tutusaus, Patricia; Mack, Thomas Sebastian; Bullinger, Lars; Schnöder, Tina M.; Polanetzki, Anja; Weinert, Sönke; Ballaschk, A.; Wang, Z; Deshpande, Anagha; Armstrong, Scott A.; Döhner, Konstanze; Fischer, Thomas

doi:10.1038/leu.2015.292

Cited by 34 publications

(56 citation statements)

References 16 publications

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“…Murine hematopoietic 32D cells (parental) and 32D cells stably expressing human FLT3‐ITD 598/599 (12) were used for in vitro experiments and have been described previously . The cells were maintained in RPMI‐1640 medium supplemented with 10% heat‐inactivated fetal calf serum (FCS) in a humidified incubator at 37°C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Targeting RIPK1 in AML cells carrying FLT3‐ITD

Hillert

Bettermann‐Bethge

Nimmagadda

et al. 2019

Intl Journal of Cancer

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Mutations of fms-like tyrosine kinase 3 (FLT3) are the most frequent mutations in acute myeloid leukemia (AML). Furthermore, the internal tandem duplication (ITD) represents the most common mutation of FLT3 in AML. To explore therapeutic strategies for AML patients carrying FLT3-ITD, we analyzed death receptor (DR) signaling networks in AML cells comprising FLT3-ITD. We have started with murine myeloid progenitor 32D cells that ectopically express human FLT3-ITD (32D-FLT3-ITD) and found that RIPK1 is strongly upregulated in these cells. Subsequently, we have shown that combinatorial treatment of 32D-FLT3-ITD cells with the SMAC mimetic BV6 and CD95L sensitizes these cells toward apoptosis and necroptosis. Moreover, combinatorial treatment with death ligands (DLs), for example, CD95L or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and BV6 enhanced cell death in primary AML blasts from patients carrying FLT3-ITD mutation. Finally, pharmacological and genetic targeting of RIPK1 inhibited DL/BV6-mediated cell death in cells with FLT3-ITD mutations. Taken together, our study suggests a promising therapeutic opportunity for AML cancer cells harboring FLT3-ITD mutation via targeting RIPK1 pathways.

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Section: Methodsmentioning

confidence: 99%

Targeting RIPK1 in AML cells carrying FLT3‐ITD

Hillert

Bettermann‐Bethge

Nimmagadda

et al. 2019

Intl Journal of Cancer

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“…9,10 FLT3 belongs to the type III family of receptor tyrosine kinases. [12][13][14] In patients with acute myeloid leukaemia (AML), FLT3 is frequently mutated and is thus associated with poor prognosis and reduced survival of patients. 12 It is expressed chiefly in dendritic cells and human haematopoietic progenitors and has important function in division, differentiation and survival of the leukaemic cells.…”

Section: Introductionmentioning

confidence: 99%

“…11 The gene coding for FLT3 is present on chromosome 13.q12. 12 It is expressed chiefly in dendritic cells and human haematopoietic progenitors and has important function in division, differentiation and survival of the leukaemic cells. [12][13][14] In patients with acute myeloid leukaemia (AML), FLT3 is frequently mutated and is thus associated with poor prognosis and reduced survival of patients.…”

Section: Introductionmentioning

confidence: 99%

“…12 It is expressed chiefly in dendritic cells and human haematopoietic progenitors and has important function in division, differentiation and survival of the leukaemic cells. [12][13][14] In patients with acute myeloid leukaemia (AML), FLT3 is frequently mutated and is thus associated with poor prognosis and reduced survival of patients. 15,16 One of frequently observed mutations is internal tandem duplications (ITD) of the juxtamembrane domain, which cause autophosphorylation and dimerization that are ligand-independent.…”

Section: Introductionmentioning

confidence: 99%

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Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

Lin

et al. 2019

J Cellular Molecular Medi

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As a highly potent and highly selective oral inhibitor of FLT3/AXL, gilteritinib showed activity against FLT3D835 and FLT3-ITD mutations in pre-clinical testing, although its role on colorectal cancer (CRC) cells is not yet fully elucidated. We examined the activity of gilteritinib in suppressing growth of CRC and its enhancing effect on other drugs used in chemotherapy. In this study, we observed that, regardless of p53 status, treatment using gilteritinib induces PUMA in CRC cells via the NF-κB pathway after inhibition of AKT and activation of glycogen synthase kinase 3β (GSK-3β). PUMA was observed to be vital for apoptosis in CRC cells through treatment of gilteritinib.Moreover, enhancing induction of PUMA through different pathways could mediate chemosensitization by using gilteritinib. Furthermore, PUMA deficiency revoked the antitumour role of gilteritinib in vivo. Thus, our results indicate that PUMA mediates the antitumour activity of gilteritinib in CRC cells. These observations are critical for the therapeutic role of gilteritinib in CRC. K E Y W O R D SAKT/GSK-3β/NF-κB, apoptosis, colorectal cancer, gilteritinib, PUMA

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“…For kinase profiling we used an established cell line model (32D) harboring an FLT3-ITD mutation that enables cytokine-independent growth (16). 32D-FLT3-ITD cells were cultured for 24 hours in RPMI under steady-state conditions prior to FLT3-tyrosine-kinase-inhibitor (TKI) PKC412 (midostaurin) exposure (or to DMSO as diluent control).…”

mentioning

confidence: 99%

Kinomics Screening Identifies Aberrant Phosphorylation of CDC25C in FLT3-ITD-positive AML

Perner

Schnöder

Fischer

et al. 2016

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Abstract. Background/Aim: The presence of FLT3-Internal tandem duplications (ITDs) in human acute myeloid leukemia (AML) is associated with a dismal prognosis. Altered cell-cycle activity has been reported in FLT3-ITD-positive AML; however, the mechanisms by which this oncogene influences cell-cycle activity remained so far elusive. Materials and MethodsAcute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal selection and accumulation of mutations during disease progression (1). FLT3 is one of the most frequently mutated genes in adult AML (2-4) that encodes for a receptor tyrosine kinase required for maintenance of normal hematopoiesis (5). During leukemia development, the occurrence of FLT3-internal tandem duplications (ITD) induces constitutive activation of the encoded receptor tyrosine kinase and leads to activation of downstream effectors, such as STAT5, ERK and AKT. Depending on cooperating oncogenic events, presence of FLT3-ITD may be associated with a poor prognosis in patients with AML (2, 6, 7). Recent reports also suggested that constitutive activation of FLT3-signaling might result in aberrant cell-cycle activity (8).Stringent regulation of cell-cycle activity is of major importance to ensure proper development of hematopoiesis and to orchestrate tissue regeneration. Conversely, deregulation of cell cycle-relevant proteins can promote the development of cancer (9, 10). The final steps during cell-cycle transition are controlled by cyclin-dependent kinases (CDKs) in complex with the appropriate cyclins. CDKs are preserved in an inactive state through phosphorylation of distinct amino acid residues. Several amino acid residues need to be dephosphorylated by cell division cycle 25 (CDC25) phosphatases (9, 10) to activate CDKs. Therefore, CDC25 phosphatases are essential regulators of cell cycle progression in malignant and non-malignant cells. In mammals, this group of phosphatases consists of three homologues, CDC25A, CDC25B and CDC25C. These are involved in pathogenesis of human malignancies (9, 10) and, specifically, myeloid leukemia (11, 12). While CDC25A is important for S-phase entry and, crucial for regulating cellular proliferation (13), CDC25B and CDC25C are believed to control mitosis entry (14). Taken together, all CDC25 phosphatases are involved in cell-cycle checkpoint regulation with redundant and non-redundant functions (9). Recently, frequent mutation of CDC25C has been reported in patients with familial platelet disorder (FPD). CDC25C defines a preleukemic clone, which eventually acquires additional mutations during disease progression. Of note, the observed CDC25C mutations are exclusively found in FPD patients rather than in de novo AML or myelodysplastic syndromes (MDSs) (15). Here, we provide first evidence that FLT3-ITD induces aberrant phosphorylation of CDC25C that functionally mimics features observed in the mutant CDC25C isoforms of FPD patients. 6249Τhis article is freely accessible online. ANTICANCER RESEARCH 36: 6249-6258 (2016) Mat...

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Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo

Cited by 34 publications

References 16 publications

Targeting RIPK1 in AML cells carrying FLT3‐ITD

Targeting RIPK1 in AML cells carrying FLT3‐ITD

Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

Kinomics Screening Identifies Aberrant Phosphorylation of CDC25C in FLT3-ITD-positive AML

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