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Tytuł pozycji:

Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

Tytuł:
Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.
Autorzy:
Tarlock K; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. .; Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, Washington.
Alonzo TA; University of Southern California Keck School of Medicine, Los Angeles, California.; Children's Oncology Group, Monrovia, California.
Wang YC; Children's Oncology Group, Monrovia, California.
Gerbing RB; Children's Oncology Group, Monrovia, California.
Ries R; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Loken MR; Hematologics, Inc, Seattle, Washington.
Pardo L; Hematologics, Inc, Seattle, Washington.
Hylkema T; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Joaquin J; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Sarukkai L; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Raimondi SC; St Jude Children's Research Hospital, Memphis, Tennessee.
Hirsch B; University of Minnesota Cancer Center, Minneapolis, Minnesota.
Sung L; The Hospital for Sick Children, Toronto, Ontario, Canada.
Aplenc R; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Bernstein I; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, Washington.
Gamis AS; Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
Meshinchi S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, Washington.
Pollard JA; Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.
Źródło:
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Aug 15; Vol. 25 (16), pp. 5038-5048. Date of Electronic Publication: 2019 Jun 10.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Denville, NJ : The Association, c1995-
MeSH Terms:
Biomarkers, Tumor*
Mutation*
Core Binding Factors/*genetics
Leukemia, Myeloid, Acute/*genetics
Leukemia, Myeloid, Acute/*mortality
Proto-Oncogene Proteins c-kit/*genetics
Cell Line, Tumor ; Core Binding Factors/antagonists & inhibitors ; Exons ; Female ; Humans ; Leukemia, Myeloid, Acute/diagnosis ; Male ; Molecular Targeted Therapy ; Prognosis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-kit/antagonists & inhibitors
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Grant Information:
T32 CA009351 United States CA NCI NIH HHS; R01 CA114563 United States CA NCI NIH HHS; U10 CA098543 United States CA NCI NIH HHS; U10 CA180899 United States CA NCI NIH HHS; U10 CA180886 United States CA NCI NIH HHS
Molecular Sequence:
ClinicalTrials.gov NCT01407757
Substance Nomenclature:
0 (Biomarkers, Tumor)
0 (Core Binding Factors)
0 (Protein Kinase Inhibitors)
EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
Entry Date(s):
Date Created: 20190612 Date Completed: 20200819 Latest Revision: 20210714
Update Code:
20240104
PubMed Central ID:
PMC6754181
DOI:
10.1158/1078-0432.CCR-18-1897
PMID:
31182436
Czasopismo naukowe
Purpose: KIT mutations ( KIT + ) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.
Experimental Design: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [ KIT + vs. wild-type KIT ( KIT - )] and mutation location (E8 vs. E17).
Results: KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT + CBF AML had overall survival similar to those with KIT - (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT + outcomes were inferior to KIT - patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.
Conclusions: E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT + patients.
(©2019 American Association for Cancer Research.)

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