DOI: 10.1182/blood.v98.3.885. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations

A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations

10.1182/blood.v98.3.885

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

Abstract Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML.

Bibliography

Levis, M., Tse, K.-F., Smith, B. D., Garrett, E., & Small, D. (2001). A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood, 98(3), 885â887.

Authors 5

Mark Levis (first)
Kam-Fai Tse (additional)
B. Douglas Smith (additional)
Elizabeth Garrett (additional)
Donald Small (additional)

References 24 Referenced 157

10.1182/blood.V80.10.2584.2584 / Blood. / Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. by Birg (1992)
10.1182/blood.V87.3.1089.bloodjournal8731089 / Blood. / Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. by Carow (1996)
{'key': '2020021221251500700_B3', 'first-page': '378', 'article-title': 'Effects of FLT3 ligand on acute myeloid and lymphocytic leukemic blast cells from children.', 'volume': '24', 'author': 'McKenna', 'year': '1996', 'journal-title': 'Exp Hematol.'} / Exp Hematol. / Effects of FLT3 ligand on acute myeloid and lymphocytic leukemic blast cells from children. by McKenna (1996)
10.1182/blood.V88.10.3987.bloodjournal88103987 / Blood. / Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. by Lisovsky (1996)
{'key': '2020021221251500700_B5', 'first-page': '1584', 'article-title': 'Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts.', 'volume': '10', 'author': 'Stacchini', 'year': '1996', 'journal-title': 'Leukemia.'} / Leukemia. / Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts. by Stacchini (1996)
{'key': '2020021221251500700_B6', 'first-page': '588', 'article-title': 'Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells.', 'volume': '10', 'author': 'Drexler', 'year': '1996', 'journal-title': 'Leukemia.'} / Leukemia. / Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. by Drexler (1996)
{'key': '2020021221251500700_B7', 'first-page': '261', 'article-title': 'Effects of FLT3 ligand on human leukemia cells, I: proliferative response of myeloid leukemia cells.', 'volume': '10', 'author': 'Dehmel', 'year': '1996', 'journal-title': 'Leukemia.'} / Leukemia. / Effects of FLT3 ligand on human leukemia cells, I: proliferative response of myeloid leukemia cells. by Dehmel (1996)
{'key': '2020021221251500700_B8', 'first-page': '1911', 'article-title': 'Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia.', 'volume': '10', 'author': 'Nakao', 'year': '1996', 'journal-title': 'Leukemia.'} / Leukemia. / Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. by Nakao (1996)
10.1038/sj.leu.2401731 / Leukemia. / Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the FLT3 gene. by Rombouts (2000)
{'key': '2020021221251500700_B10', 'first-page': '825a', 'article-title': 'The presence of a FLT3 mutation in AML adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the MRC AML 10 and 12 trials.', 'volume': '96', 'author': 'Kottaridis', 'year': '2000', 'journal-title': 'Blood.'} / Blood. / The presence of a FLT3 mutation in AML adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the MRC AML 10 and 12 trials. by Kottaridis (2000)
10.1038/sj.leu.2401130 / Leukemia. / Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. by Kiyoi (1998)
{'key': '2020021221251500700_B12', 'first-page': '3074', 'article-title': 'Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.', 'volume': '93', 'author': 'Kiyoi', 'year': '1999', 'journal-title': 'Blood.'} / Blood. / Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. by Kiyoi (1999)
10.1182/blood.V97.1.89 / Blood. / Prevalence and prognostic significance of fLT3 internal tandem duplication in pediatric acute myeloid leukemia. by Meshinchi (2001)
10.1038/sj.leu.2401905 / Leukemia. / Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. by Tse (2000)
10.1038/sj.onc.1203354 / Oncogene. / Tandem-duplicated FLT3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. by Hayakawa (2000)
10.1182/blood.V96.12.3907 / Blood. / FLT3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. by Mizuki (2000)
10.1021/jm950727b / J Med Chem. / Tyrphostins, 5: potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins. by Gazit (1996)
{'key': '2020021221251500700_B18', 'first-page': '6106', 'article-title': 'Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation.', 'volume': '54', 'author': 'Kovalenko', 'year': '1994', 'journal-title': 'Cancer Res.'} / Cancer Res. / Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. by Kovalenko (1994)
10.1111/j.1600-0609.1998.tb01017.x / Eur J Haematol. / Inv(16) acute myeloid leukemia cells show an increased sensitivity to cytosine arabinoside in vitro. by Tosi (1998)
{'key': '2020021221251500700_B20'}
10.1111/j.1600-0609.1999.tb01881.x / Eur J Haematol. / Leukaemia cell drug resistance and prognostic factors in AML. by Norgaard (1999)
{'key': '2020021221251500700_B22', 'first-page': '2879', 'article-title': 'Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia.', 'volume': '96', 'author': 'Zwaan', 'year': '2000', 'journal-title': 'Blood.'} / Blood. / Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. by Zwaan (2000)
10.1182/blood.V59.6.1351.1351 / Blood. / Pharmacokinetics of continuous intravenous and subcutaneous infusions of cytosine arabinoside. by Weinstein (1982)
10.1172/JCI9083 / J Clin Invest. / Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. by Druker (2000)

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 4:46 a.m.)
Deposited	5 years, 6 months ago (Feb. 12, 2020, 4:26 p.m.)
Indexed	5 days, 19 hours ago (Aug. 31, 2025, 6:30 a.m.)
Issued	24 years, 1 month ago (Aug. 1, 2001)
Published	24 years, 1 month ago (Aug. 1, 2001)
Published Print	24 years, 1 month ago (Aug. 1, 2001)

Funders 0

None

BibTeX

@article{Levis_2001, title={A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations}, volume={98}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v98.3.885}, DOI={10.1182/blood.v98.3.885}, number={3}, journal={Blood}, publisher={American Society of Hematology}, author={Levis, Mark and Tse, Kam-Fai and Smith, B. Douglas and Garrett, Elizabeth and Small, Donald}, year={2001}, month=aug, pages={885–887} }

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