scholarly journals Distinct classes of c-Kit–activating mutations differ in their ability to promote RUNX1-ETO–associated acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1522-1531 ◽  
Author(s):  
Heidi J. Nick ◽  
Hyung-Gyoon Kim ◽  
Chia-Wei Chang ◽  
Kevin W. Harris ◽  
Vishnu Reddy ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Granulocytic Sarcoma ◽  
Kinase Domain ◽  
Short Latency ◽  
Tyrosine Kinase Domain ◽  
Hematopoietic Stem ◽  
Retroviral Transduction ◽  
Acute Myeloid

Abstract The t(8;21) RUNX1-ETO translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). In RUNX1-ETO+ patient samples, differing classes of activating c-KIT receptor tyrosine kinase mutations have been observed. The most common (12%-48%) involves mutations, such as D816V, which occur in the tyrosine kinase domain, whereas another involves mutations within exon 8 in a region mediating receptor dimerization (2%-13% of cases). To test whether distinct subtypes of activating c-KIT mutations differ in their leukemogenic potential in association with RUNX1-ETO, we used a retroviral transduction/transplantation model to coexpress RUNX1-ETO with either c-KitD814V or c-KitT417IΔ418-419 in murine hematopoietic stem/progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted animals showed that RUNX1-ETO;c-KitD814V coexpression resulted in 3 nonoverlapping phenotypes. In 45% of animals, a transplantable AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative phenotype (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, RUNX1-ETO;c-KitT417IΔ418-419 coexpression promoted exclusively AML in a fraction (51%) of reconstituted mice. These observations indicate that c-KitD814V promotes a more varied and aggressive leukemic phenotype than c-KitT417IΔ418-419, which may be the result of differing potencies of the activating c-Kit alleles.

scholarly journals Frequency and Prognostic Relevance ofFLT3Mutations in Saudi Acute Myeloid Leukemia Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ghaleb Elyamany ◽  
Mohammad Awad ◽  
Kamal Fadalla ◽  
Mohamed Albalawi ◽  
Mohammad Al Shahrani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Point Mutations ◽  
Kinase Domain ◽  
High Rate ◽  
Tyrosine Kinase Domain ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that plays a key role in cell survival, proliferation, and differentiation of hematopoietic stem cells. Mutations ofFLT3were first described in 1997 and account for the most frequent molecular mutations in acute myeloid leukemia (AML). AML patients withFLT3internal tandem duplication (ITD) mutations have poor cure rates the prognostic significance of point mutations; tyrosine kinase domain (TKD) is still unclear. We analyzed the frequency ofFLT3mutations (ITD and D835) in patients with AML at diagnosis; no sufficient data currently exist regardingFLT3mutations in Saudi AML patients. This study was aimed at evaluating the frequency ofFLT3mutations in patients with AML and its significance for prognosis. The frequency ofFLT3mutations in our study (18.56%) was lower than many of the reported studies,FLT3-ITD mutations were observed in 14.4%, andFLT3-TKD in 4.1%, of 97 newly diagnosed AML patients (82 adult and 15 pediatric). Our data show significant increase ofFLT3mutations in male more than female (13 male, 5 female). Our results support the view thatFLT3-ITD mutation has strong prognostic factor in AML patients and is associated with high rate of relapse, and high leucocytes and blast count at diagnosis and relapse.

scholarly journals Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3-tyrosine kinase domain mutations

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2142-2149 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Kinase Domain Mutations ◽  
Acute Myeloid

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.

Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain

Blood ◽  
2005 ◽  
Vol 107 (1) ◽  
pp. 293-300 ◽  
Author(s):  
Florian Heidel ◽  
Fian K. Solem ◽  
Frank Breitenbuecher ◽  
Daniel B. Lipka ◽  
Stefan Kasper ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Clinical Resistance ◽  
Acute Myeloid

scholarly journals Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Juanjuan Zhao ◽  
Yongping Song ◽  
Delong Liu
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Salvage Chemotherapy ◽  
Tyrosine Kinase Domain ◽  
Dual Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

scholarly journals Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

2020 ◽  
Vol 10 ◽  
Author(s):  
Kran Suknuntha ◽  
Yoon Jung Choi ◽  
Ho Sun Jung ◽  
Aditi Majumder ◽  
Sujal Shah ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Kinase Domain ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Numerous recurrent genetic mutations are known to occur in acute myeloid leukemia (AML). Among these common mutations, Fms-like tyrosine kinase 3 remains as one of the most frequently mutated genes in AML. We observed apparent marrow expansion of megakaryocytes in three out of six patients with Flt3-mutated AML following treatment with a recently FDA-approved Flt3 inhibitor, gilteritinib which possesses activity against internal tandem duplication and tyrosine kinase domain Flt3 mutations and also inhibits tyrosine kinase AXL. To assess whether biopsy findings can be attributed to promotion of megakaryocytic (Mk) differentiation with gilteritinib, we devised a cellular assay by overexpressing double mutated Flt3-ITDY591F/Y919F in chronic myeloid leukemia cell line K562 to study Mk differentiation in the presence of Flt3 and AXL inhibitors with non-mutually exclusive mechanisms. These experiments demonstrated the lack of direct effect Flt3 inhibitors gilteritinib and quizartinib on megakaryocytic differentiation at either transcriptional or phenotypic levels, and highlighted antileukemic effects of AXL receptor tyrosine kinase inhibitor and its potential role in megakaryocytic development.

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