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

Puissant, Alexandre; Fenouille, Nina; Alexe, Gabriela; Pikman, Yana; Bassil, Christopher F; Mehta, Swapnil; Du, Jinyan; Kazi, Julhash U. LU ; Luciano, Frédéric and Rönnstrand, Lars LU , et al. (2014) In Cancer Cell 25(2). p.226-242
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... (More)
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. (Less)
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publication status
published
subject
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Cancer Cell
volume
25
issue
2
pages
226 - 242
publisher
Cell Press
external identifiers
  • pmid:24525236
  • wos:000331498000010
  • scopus:84893550362
ISSN
1878-3686
DOI
10.1016/j.ccr.2014.01.022
language
English
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yes
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d2a9228e-fd42-4648-9609-df00a2e9fdd7 (old id 4334651)
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http://www.ncbi.nlm.nih.gov/pubmed/24525236?dopt=Abstract
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2014-03-05 23:55:24
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2017-11-05 03:18:36
@article{d2a9228e-fd42-4648-9609-df00a2e9fdd7,
  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       = {Puissant, Alexandre and Fenouille, Nina and Alexe, Gabriela and Pikman, Yana and Bassil, Christopher F and Mehta, Swapnil and Du, Jinyan and Kazi, Julhash U. and Luciano, Frédéric and Rönnstrand, Lars and Kung, Andrew L and Aster, Jon C and Galinsky, Ilene and Stone, Richard M and Deangelo, Daniel J and Hemann, Michael T and Stegmaier, Kimberly},
  issn         = {1878-3686},
  language     = {eng},
  number       = {2},
  pages        = {226--242},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.},
  url          = {http://dx.doi.org/10.1016/j.ccr.2014.01.022},
  volume       = {25},
  year         = {2014},
}