SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.

Alexandre Puissant; Nina Fenouille; Gabriela Alexe; Yana Pikman; Christopher F Bassil; Swapnil Mehta; Jinyan Du; Julhash U. Kazi; Frédéric Luciano; Lars Rönnstrand; Andrew L Kung; Jon C Aster; Ilene Galinsky; Richard M Stone; Daniel J Deangelo; Michael T Hemann; Kimberly Stegmaier

doi:10.1016/j.ccr.2014.01.022

SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.

Alexandre Puissant, Nina Fenouille, Gabriela Alexe, Yana Pikman, Christopher F Bassil, Swapnil Mehta, Jinyan Du, Julhash U. Kazi, Frédéric Luciano, Lars Rönnstrand, Andrew L Kung, Jon C Aster, Ilene Galinsky, Richard M Stone, Daniel J Deangelo, Michael T Hemann, Kimberly Stegmaier

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

Abstract

Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.

Original language	English
Pages (from-to)	226-242
Journal	Cancer Cell
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2014.01.022
Publication status	Published - 2014

Subject classification (UKÄ)

Cancer and Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2014.01.022

http://www.ncbi.nlm.nih.gov/pubmed/24525236?dopt=Abstract

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Puissant, A., Fenouille, N., Alexe, G., Pikman, Y., Bassil, C. F., Mehta, S., Du, J., Kazi, J. U., Luciano, F., Rönnstrand, L., Kung, A. L., Aster, J. C., Galinsky, I., Stone, R. M., Deangelo, D. J., Hemann, M. T., & Stegmaier, K. (2014). SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia. Cancer Cell, 25(2), 226-242. https://doi.org/10.1016/j.ccr.2014.01.022

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title = "SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.",

abstract = "Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.",

author = "Alexandre Puissant and Nina Fenouille and Gabriela Alexe and Yana Pikman and Bassil, {Christopher F} and Swapnil Mehta and Jinyan Du and Kazi, {Julhash U.} and Fr{\'e}d{\'e}ric Luciano and Lars R{\"o}nnstrand and Kung, {Andrew L} and Aster, {Jon C} and Ilene Galinsky and Stone, {Richard M} and Deangelo, {Daniel J} and Hemann, {Michael T} and Kimberly Stegmaier",

year = "2014",

doi = "10.1016/j.ccr.2014.01.022",

language = "English",

volume = "25",

pages = "226--242",

journal = "Cancer Cell",

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T1 - SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.

AU - Puissant, Alexandre

AU - Fenouille, Nina

AU - Alexe, Gabriela

AU - Pikman, Yana

AU - Bassil, Christopher F

AU - Mehta, Swapnil

AU - Du, Jinyan

AU - Kazi, Julhash U.

AU - Luciano, Frédéric

AU - Rönnstrand, Lars

AU - Kung, Andrew L

AU - Aster, Jon C

AU - Galinsky, Ilene

AU - Stone, Richard M

AU - Deangelo, Daniel J

AU - Hemann, Michael T

AU - Stegmaier, Kimberly

PY - 2014

Y1 - 2014

N2 - Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.

AB - Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.

U2 - 10.1016/j.ccr.2014.01.022

DO - 10.1016/j.ccr.2014.01.022

M3 - Article

SN - 1878-3686

VL - 25

SP - 226

EP - 242

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.

Abstract

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UN SDGs

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