Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification

Scott A Armstrong; Andrew L Kung; Meghann E Mabon; Lewis B Silverman; Ronald W Stam; Monique L Den Boer; Rob Pieters; John H Kersey; Stephen E Sallan; Jonathan A Fletcher; Todd R Golub; James D Griffin; Stanley J Korsmeyer

doi:10.1016/s1535-6108(03)00003-5

Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification

Scott A Armstrong, Andrew L Kung, Meghann E Mabon, Lewis B Silverman, Ronald W Stam, Monique L Den Boer, Rob Pieters, John H Kersey, Stephen E Sallan, Jonathan A Fletcher, Todd R Golub, James D Griffin, Stanley J Korsmeyer

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

358 Citations (Scopus)

Abstract

We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.

Original language	English
Pages (from-to)	173-83
Number of pages	11
Journal	Cancer cell
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/s1535-6108(03)00003-5
Publication status	Published - Feb 2003
Externally published	Yes

Keywords

Animals
Annexin A5/metabolism
Antineoplastic Agents/pharmacology
Child, Preschool
DNA-Binding Proteins/genetics
Female
Gene Expression
Histone-Lysine N-Methyltransferase
Humans
In Situ Hybridization, Fluorescence
Interleukin-3/metabolism
Mice
Myeloid-Lymphoid Leukemia Protein
Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology
Protein Kinase C/antagonists & inhibitors
Proto-Oncogene Proteins/antagonists & inhibitors
Proto-Oncogenes
Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
Reverse Transcriptase Polymerase Chain Reaction
Staurosporine/analogs & derivatives
Transcription Factors
Transfection
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3

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10.1016/s1535-6108(03)00003-5

Cite this

Armstrong, S. A., Kung, A. L., Mabon, M. E., Silverman, L. B., Stam, R. W., Den Boer, M. L., Pieters, R., Kersey, J. H., Sallan, S. E., Fletcher, J. A., Golub, T. R., Griffin, J. D., & Korsmeyer, S. J. (2003). Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification. Cancer cell, 3(2), 173-83. https://doi.org/10.1016/s1535-6108(03)00003-5

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title = "Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification",

abstract = "We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.",

keywords = "Animals, Annexin A5/metabolism, Antineoplastic Agents/pharmacology, Child, Preschool, DNA-Binding Proteins/genetics, Female, Gene Expression, Histone-Lysine N-Methyltransferase, Humans, In Situ Hybridization, Fluorescence, Interleukin-3/metabolism, Mice, Myeloid-Lymphoid Leukemia Protein, Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology, Protein Kinase C/antagonists & inhibitors, Proto-Oncogene Proteins/antagonists & inhibitors, Proto-Oncogenes, Receptor Protein-Tyrosine Kinases/antagonists & inhibitors, Reverse Transcriptase Polymerase Chain Reaction, Staurosporine/analogs & derivatives, Transcription Factors, Transfection, Tumor Cells, Cultured, fms-Like Tyrosine Kinase 3",

author = "Armstrong, {Scott A} and Kung, {Andrew L} and Mabon, {Meghann E} and Silverman, {Lewis B} and Stam, {Ronald W} and {Den Boer}, {Monique L} and Rob Pieters and Kersey, {John H} and Sallan, {Stephen E} and Fletcher, {Jonathan A} and Golub, {Todd R} and Griffin, {James D} and Korsmeyer, {Stanley J}",

note = "Funding Information: We thank members of Novartis Pharmaceuticals PKC412 development team. We also thank Julie Kujawa and Elizabeth Tanner for help with the mouse studies, Eric Smith for help with editing, and Stephen Lessnick for help with retrovirus production. This work was supported in part by NIH grants PO1 CA68484 and KO8 CA92551 and an American Society of Hematology Fellow Scholar Award (S.A.A.).",

year = "2003",

month = feb,

doi = "10.1016/s1535-6108(03)00003-5",

language = "English",

volume = "3",

pages = "173--83",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Armstrong, SA, Kung, AL, Mabon, ME, Silverman, LB, Stam, RW , Den Boer, ML , Pieters, R, Kersey, JH, Sallan, SE, Fletcher, JA, Golub, TR, Griffin, JD & Korsmeyer, SJ 2003, 'Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification', Cancer cell, vol. 3, no. 2, pp. 173-83. https://doi.org/10.1016/s1535-6108(03)00003-5

Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification. / Armstrong, Scott A; Kung, Andrew L; Mabon, Meghann E et al.
In: Cancer cell, Vol. 3, No. 2, 02.2003, p. 173-83.

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

TY - JOUR

T1 - Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification

T2 - Validation of a therapeutic target identified by gene expression based classification

AU - Armstrong, Scott A

AU - Kung, Andrew L

AU - Mabon, Meghann E

AU - Silverman, Lewis B

AU - Stam, Ronald W

AU - Den Boer, Monique L

AU - Pieters, Rob

AU - Kersey, John H

AU - Sallan, Stephen E

AU - Fletcher, Jonathan A

AU - Golub, Todd R

AU - Griffin, James D

AU - Korsmeyer, Stanley J

N1 - Funding Information: We thank members of Novartis Pharmaceuticals PKC412 development team. We also thank Julie Kujawa and Elizabeth Tanner for help with the mouse studies, Eric Smith for help with editing, and Stephen Lessnick for help with retrovirus production. This work was supported in part by NIH grants PO1 CA68484 and KO8 CA92551 and an American Society of Hematology Fellow Scholar Award (S.A.A.).

PY - 2003/2

Y1 - 2003/2

N2 - We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.

AB - We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.

KW - Animals

KW - Annexin A5/metabolism

KW - Antineoplastic Agents/pharmacology

KW - Child, Preschool

KW - DNA-Binding Proteins/genetics

KW - Female

KW - Gene Expression

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Interleukin-3/metabolism

KW - Mice

KW - Myeloid-Lymphoid Leukemia Protein

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology

KW - Protein Kinase C/antagonists & inhibitors

KW - Proto-Oncogene Proteins/antagonists & inhibitors

KW - Proto-Oncogenes

KW - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Staurosporine/analogs & derivatives

KW - Transcription Factors

KW - Transfection

KW - Tumor Cells, Cultured

KW - fms-Like Tyrosine Kinase 3

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U2 - 10.1016/s1535-6108(03)00003-5

DO - 10.1016/s1535-6108(03)00003-5

M3 - Article

C2 - 12620411

SN - 1535-6108

VL - 3

SP - 173

EP - 183

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification: Validation of a therapeutic target identified by gene expression based classification

Abstract

Keywords

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