scholarly journals An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

2012 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Tiziana Grafone ◽  
Michela Palmisano ◽  
Chiara Nicci ◽  
Sergio Storti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Molecular Therapy ◽  
Tyrosine Kinase Receptor ◽  
Hematopoietic Stem ◽  
Downstream Signaling ◽  
Proliferation And Differentiation ◽  
Acute Myeloid

Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The <em>FLT3</em> gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.

scholarly journals Maintenance therapy for FLT3-ITD-mutated acute myeloid leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Andreas Burchert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Hematopoietic Stem ◽  
Therapeutic Concept ◽  
Treatment Paradigm ◽  
Acute Myeloid

FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. This review describes key milestones in the clinical development of different FLT3-specific TKI with a particular focus on FLT3-TKI maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT). Recent evidence from randomized trials using sorafenib in FLT3-ITD mutated AML provided a proof of concept that targeted post-HCT maintenance therapy could become a new treatment paradigm in AML.

scholarly journals Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

2018 ◽  
Vol 19 (10) ◽  
pp. 3198 ◽  
Author(s):  
Dilana Staudt ◽  
Heather Murray ◽  
Tabitha McLachlan ◽  
Frank Alvaro ◽  
Anoop Enjeti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Driver Mutations ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Therapeutic Approaches ◽  
Acute Myeloid

The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.

scholarly journals FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activation

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 5034-5043 ◽  
Author(s):  
Goichi Yoshimoto ◽  
Toshihiro Miyamoto ◽  
Siamak Jabbarzadeh-Tabrizi ◽  
Tadafumi Iino ◽  
Jennifer L. Rocnik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Myeloid Cell ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34+CD38− LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3–internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)–docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.

The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2315-2323 ◽  
Author(s):  
Thomas Prebet ◽  
Anne-Catherine Lhoumeau ◽  
Christine Arnoulet ◽  
Anaïs Aulas ◽  
Sylvie Marchetto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Polarity ◽  
Myeloid Leukemia ◽  
Planar Cell Polarity ◽  
Bone Marrow Cells ◽  
Tyrosine Kinase Receptor ◽  
Epithelial Tissue ◽  
Tissue Organization ◽  
Acute Myeloid

Abstract The pseudo tyrosine kinase receptor 7 (PTK7) is an orphan tyrosine kinase receptor assigned to the planar cell polarity pathway. It plays a major role during embryogenesis and epithelial tissue organization. Here we found that PTK7 is also expressed in normal myeloid progenitors and CD34+ CD38− bone marrow cells in humans. We performed an immunophenotyping screen on more than 300 patients treated for hematologic malignancies. We demonstrated that PTK7 is expressed in acute myeloid leukemia (AML) and is mostly assigned to granulocytic lineage differentiation. Patients with PTK7-positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced leukemia-free survival in a multivariate analysis model. In vitro, expression of PTK7 in cultured leukemia cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis. The intracellular region of PTK7 is required for these effects. Furthermore, we efficiently sensitized primary AML blasts to anthracycline-mediated cell death using a recombinant soluble PTK7-Fc protein. We conclude that PTK7 is a planar cell polarity component expressed in the myeloid progenitor compartment that conveys promigratory and antiapoptotic signals into the cell and that represents an independent prognosis factor of survival in patients treated with induction chemotherapy.

Final Results of A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Quizartinib (AC220) Administered Daily to Patients with Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FLT3-ITD Status

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1507-1507 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
James M. Foran ◽  
Darejan Ghirdaladze ◽  
Mamia Zodelava ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Qt Interval ◽  
Myeloid Leukemia ◽  
Cell Transplant ◽  
Interval Prolongation ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Abstract 1507 FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib is an oral FLT3 receptor tyrosine kinase (RTK) inhibitor that inhibits both ITD-mutant and wild-type FLT3 and displays efficacy in preclinical models of AML. In this first-in-human study, quizartinib was evaluated in patients with relapsed or refractory AML who were enrolled irrespective of FLT3-ITD status. Quizartinib was administered orally on an intermittent schedule (ID, 14 days on, 14 days off) at 12–450 mg/day or continuously (CD) at 200 or 300 mg/day. A total of 76 patients (61% male; 90% white; median age 60 years [23–86]) received quizartinib; median number of prior treatments was 3 (0–12), including 16% with a prior hematopoietic stem cell transplant. FLT3-ITD status was 22% positive (+) (n=17), 49% negative (−) (n=37), and 29% indeterminate/not tested (ind) (n=22). Plasma inhibitory activity assays using plasma samples collected at trough timepoints showed a high degree of FLT3 inhibition at low dose levels (18 mg/day and higher), indicative of potent in vivo FLT3 inhibition. Marked inhibition of FLT3 phosphorylation was also demonstrated in peripheral blood following administration of quizartinib. Responses were observed in 23/76 patients (30%), with 10 patients (13%) having a best response of any type of complete remission (CR=morphologic leukemia-free state with absolute neutrophil count >1×109/L and platelet count ≥100×109/L, and normal marrow differential with <5% blasts with no Auer rods; CRp=CR with incomplete platelet recovery; CRi=CR with incomplete hematologic recovery). Responses included 2 CR, 3 CRp, 5 CRi, and 13 (17%) partial remissions (PR, same hematologic values as CR but with a decrease of '50% in % blasts in the bone marrow aspirate to 5% to 25%; a value of <5% blasts was considered a PR if Auer rods were present). Responses were observed at doses as low as 18 mg/day ID. Nine of 17 FLT3-ITD(+) patients responded (53%; 1 CR, 1 CRp, 2 CRi, 5 PR) compared to 5/37 FLT3-ITD(−) patients (14%; 2 CRp, 3 PR) and 9/22 with FLT3-ITD(ind) status (41%; 1 CR, 3 CRi, 5 PR). Median duration of response was 13.3 weeks (95% confidence interval [CI]: 11.0, 29.0 weeks): 9.7 weeks for FLT3-ITD(+) patients (95% CI: 4.1, 29); 23.7 weeks for FLT3-ITD(−) patients (95% CI: 11, not reached); and 12.4 weeks for FLT3-ITD(ind) patients(95% CI: 8, 53). Median overall survival was 14.0 weeks (95% CI: 10.9, 18.6 weeks): 18.3 weeks for FLT3-ITD(+) patients (95% CI: 10.6, 27.1); 9.7 weeks for FLT3-ITD(−) patients (95% CI: 5.6, 14.0); and 18.7 weeks for FLT3-ITD(ind) patients (95% CI: 14.0, 21.1). Quizartinib was generally well tolerated. The most common drug-related AEs (>10% incidence) were nausea (16%), prolonged ECG QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤Grade 2. The maximum tolerated dose was 200 mg/day CD. The dose-limiting toxicity was QTcF interval prolongation, which occurred in 38% of subjects at 300 mg/day CD and in 6% at 200 mg/day CD. QTcF interval prolongation was dose dependent, and there were no associated arrhythmias. Grade 3 AEs related to quizartinib occurring in >1 patient were prolonged ECG QT interval (4 patients [5%]), anemia (3 patients [4%]), and fatigue (2 patients [3%]). Two treatment-related Grade 4 AEs (thrombocytopenia and hypoalbuminemia) were reported in 1 patient each (1%). The encouraging efficacy results in both FLT3-ITD(+) and FLT3 ITD(−) patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib with lower doses. A recent 333 patient Phase 2 study in a similar population given quizartinib at 200, 135, or 90 mg/day has been completed, and, considering the clinical activity observed at low doses, quizartinib is also being studied in patients with relapsed or refractory AML at 30 and 60 mg/day. Disclosures: Cortes: Novartis: Consultancy. Kantarjian:Ambit Biosciences: Consultancy. Foran:Ambit Biosciences: Consultancy. Ghirdaladze:Ambit Biosciences: Consultancy. Zodelava:Ambit Biosciences: Consultancy. Borthakur:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. James:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.

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