Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

Stefan Fröhling; Claudia Scholl; Ross L. Levine; Marc Loriaux; Titus J. Boggon; Olivier A. Bernard; Roland Berger; Hartmut Döhner; Konstanze Döhner; Benjamin L. Ebert; Sewit Teckie; Todd R. Golub; Jingrui Jiang; Marcus M. Schittenhelm; Benjamin H. Lee; James D. Griffin; Richard M. Stone; Michael C. Heinrich; Michael W. Deininger; Brian J. Druker; D. Gary Gilliland

doi:10.1016/j.ccr.2007.11.005

Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

Stefan Fröhling
, Claudia Scholl
, Ross L. Levine
, Marc Loriaux
, Titus J. Boggon
, Olivier A. Bernard
, Roland Berger
, Hartmut Döhner
, Konstanze Döhner
, Benjamin L. Ebert
, Sewit Teckie
, Todd R. Golub
, Jingrui Jiang
, Marcus M. Schittenhelm
, Benjamin H. Lee
, James D. Griffin
, Richard M. Stone
, Michael C. Heinrich
, Michael W. Deininger
, Brian J. Druker

D. Gary Gilliland

Research output: Contribution to journal › Article › peer-review

174 Scopus citations

Abstract

Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.

Original language	English (US)
Pages (from-to)	501-513
Number of pages	13
Journal	Cancer Cell
Volume	12
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2007.11.005
State	Published - Dec 6 2007

Funding

We are grateful to Maricel Gozo for technical support and to Jeffrey C. Lee, Matthew Meyerson, J. Guillermo Páez, and William R. Sellers for assistance with the kinase sequencing platform. This work was supported by National Institutes of Health grants HL082677 (to R.L.L.), CA113434 (to B.H.L.), CA66996 (to D.G.G.), and CA105423 (to D.G.G.), a Veterans Affairs Merit Review Grant (to M.C.H.), and grants from the Doris Duke Charitable Foundation (to M.C.H., B.J.D., and D.G.G.) and the Leukemia and Lymphoma Society (to B.J.D. and D.G.G.). S.F. and C.S. are supported by grants from the Deutsche Forschungsgemeinschaft. R.L.L. is the recipient of an American Society of Hematology Basic Research Fellow Award, an American Society of Clinical Oncology Young Investigator Award, and a Doris Duke Charitable Foundation Clinical Development Scientist Award. T.J.B. is the recipient of an American Society of Hematology Junior Faculty Scholar Award. M.M.S. is supported by grants from the Deutsche Krebshilfe and the Fortüne Program of the University of Tübingen. D.G.G. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. M.C.H. and B.J.D. are scientific founders of MolecularMD, a company that specializes in the development of molecular assays for leukemias, lymphomas, and solid tumors. All other authors declare that they have no competing financial interests.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	CA105423, CA66996, CA113434
National Institute of Health National Heart, Lung, and Blood Institute	K08HL082677
Doris Duke Charitable Foundation
American Society of Hematology Minority Hematology
Leukemia and Lymphoma Society
American Society of Clinical Oncology
Deutsche Forschungsgemeinschaft
Eberhard-Karls-Universität Tübingen
Ministry of Patriots and Veterans Affairs
Deutsche Krebshilfe

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccr.2007.11.005

Cite this

Fröhling, S., Scholl, C., Levine, R. L., Loriaux, M., Boggon, T. J., Bernard, O. A., Berger, R., Döhner, H., Döhner, K., Ebert, B. L., Teckie, S., Golub, T. R., Jiang, J., Schittenhelm, M. M., Lee, B. H., Griffin, J. D., Stone, R. M., Heinrich, M. C., Deininger, M. W., ... Gilliland, D. G. (2007). Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles. Cancer Cell, 12(6), 501-513. https://doi.org/10.1016/j.ccr.2007.11.005

Fröhling, S, Scholl, C, Levine, RL, Loriaux, M, Boggon, TJ, Bernard, OA, Berger, R, Döhner, H, Döhner, K, Ebert, BL, Teckie, S, Golub, TR, Jiang, J, Schittenhelm, MM, Lee, BH, Griffin, JD, Stone, RM, Heinrich, MC, Deininger, MW, Druker, BJ & Gilliland, DG 2007, 'Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles', Cancer Cell, vol. 12, no. 6, pp. 501-513. https://doi.org/10.1016/j.ccr.2007.11.005

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abstract = "Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish {"}driver{"} mutations underlying tumorigenesis from biologically neutral {"}passenger{"} alterations.",

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author = "Stefan Fr{\"o}hling and Claudia Scholl and Levine, \{Ross L.\} and Marc Loriaux and Boggon, \{Titus J.\} and Bernard, \{Olivier A.\} and Roland Berger and Hartmut D{\"o}hner and Konstanze D{\"o}hner and Ebert, \{Benjamin L.\} and Sewit Teckie and Golub, \{Todd R.\} and Jingrui Jiang and Schittenhelm, \{Marcus M.\} and Lee, \{Benjamin H.\} and Griffin, \{James D.\} and Stone, \{Richard M.\} and Heinrich, \{Michael C.\} and Deininger, \{Michael W.\} and Druker, \{Brian J.\} and Gilliland, \{D. Gary\}",

note = "Funding Information: We are grateful to Maricel Gozo for technical support and to Jeffrey C. Lee, Matthew Meyerson, J. Guillermo P{\'a}ez, and William R. Sellers for assistance with the kinase sequencing platform. This work was supported by National Institutes of Health grants HL082677 (to R.L.L.), CA113434 (to B.H.L.), CA66996 (to D.G.G.), and CA105423 (to D.G.G.), a Veterans Affairs Merit Review Grant (to M.C.H.), and grants from the Doris Duke Charitable Foundation (to M.C.H., B.J.D., and D.G.G.) and the Leukemia and Lymphoma Society (to B.J.D. and D.G.G.). S.F. and C.S. are supported by grants from the Deutsche Forschungsgemeinschaft. R.L.L. is the recipient of an American Society of Hematology Basic Research Fellow Award, an American Society of Clinical Oncology Young Investigator Award, and a Doris Duke Charitable Foundation Clinical Development Scientist Award. T.J.B. is the recipient of an American Society of Hematology Junior Faculty Scholar Award. M.M.S. is supported by grants from the Deutsche Krebshilfe and the Fort{\"u}ne Program of the University of T{\"u}bingen. D.G.G. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. M.C.H. and B.J.D. are scientific founders of MolecularMD, a company that specializes in the development of molecular assays for leukemias, lymphomas, and solid tumors. All other authors declare that they have no competing financial interests. ",

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doi = "10.1016/j.ccr.2007.11.005",

language = "English (US)",

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T1 - Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

AU - Fröhling, Stefan

AU - Scholl, Claudia

AU - Levine, Ross L.

AU - Loriaux, Marc

AU - Boggon, Titus J.

AU - Bernard, Olivier A.

AU - Berger, Roland

AU - Döhner, Hartmut

AU - Döhner, Konstanze

AU - Ebert, Benjamin L.

AU - Teckie, Sewit

AU - Golub, Todd R.

AU - Jiang, Jingrui

AU - Schittenhelm, Marcus M.

AU - Lee, Benjamin H.

AU - Griffin, James D.

AU - Stone, Richard M.

AU - Heinrich, Michael C.

AU - Deininger, Michael W.

AU - Druker, Brian J.

AU - Gilliland, D. Gary

N1 - Funding Information: We are grateful to Maricel Gozo for technical support and to Jeffrey C. Lee, Matthew Meyerson, J. Guillermo Páez, and William R. Sellers for assistance with the kinase sequencing platform. This work was supported by National Institutes of Health grants HL082677 (to R.L.L.), CA113434 (to B.H.L.), CA66996 (to D.G.G.), and CA105423 (to D.G.G.), a Veterans Affairs Merit Review Grant (to M.C.H.), and grants from the Doris Duke Charitable Foundation (to M.C.H., B.J.D., and D.G.G.) and the Leukemia and Lymphoma Society (to B.J.D. and D.G.G.). S.F. and C.S. are supported by grants from the Deutsche Forschungsgemeinschaft. R.L.L. is the recipient of an American Society of Hematology Basic Research Fellow Award, an American Society of Clinical Oncology Young Investigator Award, and a Doris Duke Charitable Foundation Clinical Development Scientist Award. T.J.B. is the recipient of an American Society of Hematology Junior Faculty Scholar Award. M.M.S. is supported by grants from the Deutsche Krebshilfe and the Fortüne Program of the University of Tübingen. D.G.G. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. M.C.H. and B.J.D. are scientific founders of MolecularMD, a company that specializes in the development of molecular assays for leukemias, lymphomas, and solid tumors. All other authors declare that they have no competing financial interests.

PY - 2007/12/6

Y1 - 2007/12/6

N2 - Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.

AB - Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.

KW - CELLCYCLE

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UR - https://www.scopus.com/pages/publications/36649000489#tab=citedBy

U2 - 10.1016/j.ccr.2007.11.005

DO - 10.1016/j.ccr.2007.11.005

M3 - Article

C2 - 18068628

AN - SCOPUS:36649000489

SN - 1535-6108

VL - 12

SP - 501

EP - 513

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

Abstract

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Keywords

ASJC Scopus subject areas

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