Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD

Okamoto, Masanori; Hayakawa, Fumihiko; Miyata, Yasuyoshi; Watamoto, K; Emi, Nobuhiko; Abe, Akihiro; Kiyoi, Hitoshi; Towatari, Masayuki; Naoe, Tomoki

doi:10.1038/sj.leu.2404547

Cited by 57 publications

(61 citation statements)

References 31 publications

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“…22 Using tyrosine kinase inhibitors and transfected murine IL-3-dependent cell lines, two studies have suggested that LYN is involved in the proliferation signal of FLT3-ITD. 23,24 This was substantiated in one of the studies by RNA interference. 24 A recent study suggests that SHP2, an upstream activator of the ERK1/2 pathway, is dispensable for FLT3-ITD-dependent proliferation and transformation.…”

Section: Discussionmentioning

confidence: 81%

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FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

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Section: Discussionmentioning

confidence: 81%

“…23,24 This was substantiated in one of the studies by RNA interference. 24 A recent study suggests that SHP2, an upstream activator of the ERK1/2 pathway, is dispensable for FLT3-ITD-dependent proliferation and transformation. 25 Furthermore, the PI3-kinase pathway seems to be dispensable for oncogenic FLT3.…”

Section: Discussionmentioning

confidence: 81%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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“…Inhibition of SFKs either by PP2 treatment or siRNA suppresses the growth of FLT3/ITD expressing 32D cells. PP2 treatment of mice injected subcutaneously with FLT3/ITD expressing 32D cells blocks tumor formation (197). Thus, in these models, it appears that SFK do not play a major role in the initiation of tumor formation but have a significant effect on tumor progression.…”

Section: Src Family Kinases and Leukemiamentioning

confidence: 91%

The diverse functions of Src family kinases in macrophages

Abram

Lowell²

2008

Front Biosci

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Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. KeywordsTyrosine kinases; signal transduction; innate immunity; integrins; Toll-like receptors; ITIM; ITAM; adhesion; migration; Hck; Fgr; Lyn; Review INTRODUCTION Src family kinases -general approachesc-Src was first described as the cellular counterpart of v-Src, the transforming gene found in Rous Sarcoma Virus, and has since been the focus of much research. Src and its other family members, referred to as Src Family Kinases (SFKs) throughout this review, have been implicated in many diverse signaling pathways in both immune (1) and non-immune cell types (2). This is apparent from the close to 25,000 PubMed hits one gets when researching these enzymes. Furthermore, a strong clinical interest has developed in SFKs based on the growing realization of their central roles in human cancer (3, 4).Src family members include c-Src, Fyn, c-Yes, Lck, Hck, c-Fgr, Lyn, Blk, and Yrk. Src, Fyn and Yes are ubiquitously expressed whereas Lck, Hck, Fgr, Lyn and Blk tend to be more restricted to cells of hematopoietic origin. Yrk has only been found in chickens. The SFKs Send correspondence to: Dr Clifford Lowell, Department of Laboratory Medicine, University of California, San Francisco, S1058, 513 Parnassus Avenue, San Francisco, CA94143-0451, Tel: 415-476-2540, Fax: 415-502-9404, clifford.lowell@ucsf.edu. HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2015 June 05. Published in final edited form as:Front Biosci. ; 13: 4426-4450. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript are cytoplasmic tyrosine kinases, consisting of an N-terminal unique domain, a Src homology 3 (SH3) domain that can interact with polyproline-rich motifs, a Src homology 2 (SH2) domain that binds phosphotyrosine residues, and a tyrosine kinase domain ( Figure 1A). Acylation of SFKs at their N-terminus (palmitoylation and/or myristoylation) al...

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“…11 Notably, LYN is involved in FLT3-internal tandem duplication signaling in AML, 12 and somatic LYN mutations were found in various solid tumors, including breast cancer and glioma (Catalogue of Somatic Mutations in CancerFCOSMIC, Sanger Institute). We also found a missense mutation in the discoidin domain receptor tyrosine kinase 2 gene (DDR2).…”

Section: Letters To the Editormentioning

confidence: 99%

Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing

et al. 2011

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tumor-bearing mice, when compared with normal control nonirradiated mice (Figures 2c and d). Furthermore, exogenous rmHMGB1 (recombinant mouse HMGB1) showed its capacity to upregulate the IL6 and miR-21 expression level in a TLR4-dependent manner (Figure 2e). These data indicate the possible important role of HMGB1/TLR4/IL6-miR-21 pathway in radiation-induced carcinogenesis.Our data presented here may provide a novel possible mechanism for split-dose radiation-induced thymic lymphomas. As shown in Figure 2f, split-dose irradiation may injure the thymus cells, inducing apoptosis and necrosis, and releasing many danger-and death-related signals like HMGB1. This in turn may activate TLR4 and elevate the pro-tumor cytokines IL6 and miR-21, together with important factors like MMP9 and miR-155, to induce carcinogenesis. To the best of our knowledge, this is the first report describing a role for TLR4 in radiation-induced thymic lymphoma in vivo. This work therefore provides some novel experimental evidence about potential therapeutic targets for the prevention and treatment of radiationinduced carcinogenesis.

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Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD

Cited by 57 publications

References 31 publications

FES kinases are required for oncogenic FLT3 signaling

FES kinases are required for oncogenic FLT3 signaling

The diverse functions of Src family kinases in macrophages

Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing

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