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{{Infobox_gene}}
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'''Cluster of differentiation antigen 135''' ('''CD135''') also known as '''fms like tyrosine kinase 3''' ('''FLT-3'''), '''receptor-type tyrosine-protein kinase FLT3''', or '''fetal liver kinase-2''' (Flk2) is a [[protein]] that in humans is encoded by the ''FLT3'' [[gene]]. FLT3 is a [[cytokine receptor]] which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the [[cytokine]] [[FMS-like tyrosine kinase 3 ligand|Flt3 ligand]] (FLT3L).
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Fms-related tyrosine kinase 3
| HGNCid = 3765
| Symbol = FLT3
| AltSymbols =; STK1; CD135; FLK2
| OMIM = 136351
| ECnumber = 
| Homologene = 3040
| MGIid = 95559
| GeneAtlas_image1 = PBB_GE_FLT3_206674_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005021 |text = vascular endothelial growth factor receptor activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007169 |text = transmembrane receptor protein tyrosine kinase signaling pathway}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2322
    | Hs_Ensembl = ENSG00000122025
    | Hs_RefseqProtein = NP_004110
    | Hs_RefseqmRNA = NM_004119
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 13
    | Hs_GenLoc_start = 27475411
    | Hs_GenLoc_end = 27572729
    | Hs_Uniprot = P36888
    | Mm_EntrezGene = 14255
    | Mm_Ensembl = ENSMUSG00000042817
    | Mm_RefseqmRNA = NM_010229
    | Mm_RefseqProtein = NP_034359
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 147641520
    | Mm_GenLoc_end = 147710644
    | Mm_Uniprot = Q2VPD1
  }}
}}
{{SI}}
{{CMG}}


{{EH}}
It is expressed on the surface of many [[hematopoietic]] progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.


[[Cluster of Differentiation|CD]]135 is a [[cytokine receptor]] expressed on the surface of [[hematopoietic]] progenitor cells.
The FLT3 gene is one of the most frequently mutated genes in [[acute myeloid leukemia]] (AML).<ref name="pmid11290608">{{cite journal | vauthors = Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T | title = Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies | journal = Blood | volume = 97 | issue = 8 | pages = 2434–9 |date=April 2001 | pmid = 11290608 | doi = 10.1182/blood.V97.8.2434 }}</ref> High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.


==Synonyms==
== Structure ==
fms-like tyrosine kinase receptor-3 (Flt3), fetal liver kinase-2 (Flk2)


==Cell Surface Marker==
FLT3 is composed of five extracellular [[immunoglobulin domain|immunoglobulin-like domains]], an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes [[glycosylation]], which promotes localization of the receptor to the membrane.<ref name="urlPathway Central: FLT3 Signaling">{{cite web | url = http://www.sabiosciences.com/pathway.php?sn=FLT3_Signaling | title = FLT3 Signaling | work = Pathway Central | publisher = SABiosciences  }}</ref>
[[Cluster of differentiation]] (CD) molecules are markers on the cell surface, as recognized by specific sets of [[antibodies]], used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the [[bone marrow]]. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) expresse high surface levels of CD135. This marker is therefore used to differentiate [[hematopoietic stem cells]] (HSC), which are CD135 negative, from MPPs, which are CD135 positive.


==Ligand==
== Function ==
CD135 is the receptor for the [[cytokine]] [[FMS-like tyrosine kinase 3 ligand|Flt3 ligand]] (Flt3L).


==Function==
CD135 is a Class III [[receptor tyrosine kinase]]. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L.<ref name="pmid21389326">{{cite journal | vauthors = Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN | title = Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex | journal = Blood | volume = 118 | issue = 1 | pages = 60–68 |date=February 2011 | pmid = 21389326 | doi = 10.1182/blood-2011-01-329532 }}</ref> The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for [[lymphocyte]] ([[B cell]] and [[T cell]]) development, but not for the development of other blood cells ([[myeloid]] development).
CD135 (AKA FMS-like tyrosine kinase 3; FLT3) is a [[receptor tyrosine kinase]] type III. When this receptor binds to Flt3L it forms a [[dimer]] with itself ([[homodimer]]) which activates signaling through [[second messengers]]. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for [[lymphocyte]] ([[B cell]] and [[T cell]]) development, but not for the development of other blood cells ([[myeloid]] development).


==Role in cancer==
Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:
CD135 is a [[proto-oncogene]], meaning that mutations of this protein can lead to cancer<ref>http://AtlasGeneticsOncology.org/Genes/FLT3ID144.html</ref>.
* TNF-Alpha ([[Tumor necrosis factor-alpha]])
* TGF-Beta ([[Transforming growth factor-beta]])
TGF-Beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.<ref name="urlPathway Central: FLT3 Signaling"/>


Acute Myelocytic Leukemia with a normal karyotype (CN-AML) represents a cytogenetic group with an intermediate prognosis but a substantial molecular and clinical heterogenecity.  Within this subgroup the presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutations predicts a less favorable outcome.  (DNA microassays are used to profile gene expression). 
== Clinical significance ==


FLT3 expression was higher in AML and acute B-ALL than in CML and acute T-ALL.  FLT3 expression in the blast phase is greater than in the accelerated phase.  FLT3 mRNA is expressed in all patients with B-ALL and AML and 90% of patients with T-ALL.  FLT3 m RNA varies widely among patients with wt-FLT3 and patients with the highest wt-FLT3 have a significantly increased risk of relapse and death.  The blasts involved also have exquisite and selective sensitivity to FLT3 inhibition in-vitro.  High wt-FLT3 is indistinguishable from FLT3ITD as a poor prognostic indicator. 
=== Cell surface marker ===


FLT3 presents in 20-30% of de novo AML.  Typically patients have normal cytogenetics, leukocytosis and monocytic differentiation.  An FLT3 "activation loop" mutation is present at D835 and is associated with AML.  FLT3 didn't correlate with the FAB subtype.  Complete responses to therapy weren't different between patients with and without FLT3 but a +FLT3 had a higher relapse rate and decreased overall survival.  A lack of effect of FLT3ITD mutation on the complete response rate might be explained by the lack of effect of the FLT3ITD mutation on chemosensitivity. An analysis of the FLT3ITD allelic ratio has prognostic capacity. A low ratio (<0.2) denotes more responsiveness; a high ratio (>0.78) means a low response and increased risk of relapse. 
[[Cluster of differentiation]] (CD) molecules are markers on the cell surface, as recognized by specific sets of [[antibody|antibodies]], used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the [[bone marrow]]. Specifically, [[progenitor cell|multipotent progenitor]]s (MPP) and [[common lymphoid progenitor]]s (CLP) express high surface levels of CD135. This marker is therefore used to differentiate [[hematopoietic stem cells]] (HSC), which are CD135 negative, from MPPs, which are CD135 positive.{{citation needed|date=December 2012}} (See [[Lymphopoiesis#Labeling lymphopoiesis]])


Among the most common mutations found in cytogenetically normal (CN-AML) are those of the FMS-like tyrosine kinase 3 (FLT3) genes, namely, FLT3-internal tandem duplications (of the juxtamembrane region; ITD) and FLT3 tyrosine kinase domain (point) mutations (TKD).  Both of these mutations induce change in the FLT3, which is a gene that encodes for a tyrosine kinase receptor.  FLT3ITD induced aberrant signaling includes the strong activation of a signal transducer and activator of transcription 5 (STAT5).  FLT3TKD cannot induce or activate STAT5 target genes.  When the gene is mutated its mechanism is similar to that of a mutated KIT; it activates the abnormal mechanism of myeloblast proliferation and survival.  FLT3ITD is an independent prognostic factor and probably one of the most important molecular prognostic markers in AML, particularly in CN-AML.  The incidence of FLT3TKD is much less (~5-6%) in CN-AML. 
=== Role in cancer ===


==See also==
CD135 is a [[proto-oncogene]], meaning that mutations of this protein can lead to cancer.<ref name="urlFLT3 (FMS-like tyrosine kinase 3)">{{cite web | url = http://atlasgeneticsoncology.org/Genes/FLT3ID144.html | title = FLT3 (FMS-like tyrosine kinase 3) | author = Huret J-L | work = Atlas of Genetics and Cytogenetics in Oncology and Haematology | publisher = University Hospital of Poitiers }}</ref> [[Mutations]] of the FLT3 receptor can lead to the development of [[leukemia]], a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with [[acute myelogenous leukemia]] (AML) and are a  [[prognosis|prognostic indicator]] associated with adverse disease outcome.
 
=== FLT3 inhibitors ===
 
[[Gilteritinib]], a dual [[FLT3]]-AXL tyrosine kinase inhibitor is currently in multiple Phase III trials in [[acute myeloid leukemia]] (AML).<ref>{{Cite web|url=https://clinicaltrials.gov/ct2/results?cond=&term=&type=&rslt=&age_v=&gndr=&intr=Gilteritinib&titles=&outc=&spons=&lead=&id=&cntry=&state=&city=&dist=&locn=&phase=2&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&lupd_s=&lupd_e=}}</ref> In 2017, gilteritinib gained FDA [[orphan drug status]] for AML.<ref>{{cite web|url=http://www.cancertherapyadvisor.com/hematologic-cancers/acute-leukemia-aml-gilteritinib-fda-orphan-drug-status/article/676474/|title=Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia|date=20 July 2017|publisher=}}</ref>
 
[[Quizartinib]] (AC220) had good results in a phase II clinical trial for AML patients with FLT3 mutations.<ref name="urlEfficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML) - Full Text View -">{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00989261 | title = Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)  | work =  ClinicalTrials.gov | publisher = U.S. National Institutes of Health }}</ref> for refractory AML – particularly in patients who went on to have a stem cell transplant.<ref name="urlDrug Tames Refractory AML">{{cite web | url = http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36351 | title = Drug Tames Refractory AML | author = Gever J | date = 2012-12-09  | format = | work = ASH: Hematology Latest News | publisher = MedPage Today, LLC  }}</ref>
 
[[Midostaurin]] was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.<ref>{{Cite web |url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm555778.htm |title=Press Announcements - FDA approves new combination treatment for acute myeloid leukemia |last=Commissioner|first=Office of the|website=www.fda.gov |language=en|access-date=2017-05-04}}</ref> The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.
 
[[Sorafenib]] has been reported to show significant activity against Flt3-ITD positive [[acute myelogenous leukemia]].<ref name="pmid19389879">{{cite journal | vauthors = Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A | title = Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation | journal = Blood | volume = 113 | issue = 26 | pages = 6567–71 |date=June 2009 | pmid = 19389879 | doi = 10.1182/blood-2009-03-208298 }}</ref><ref name="pmid18230792">{{cite journal | vauthors = Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, Estrov Z, Quintás-Cardama A, Small D, Cortes J, Andreeff M | title = Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia | journal = J. Natl. Cancer Inst. | volume = 100 | issue = 3 | pages = 184–98 |date=February 2008 | pmid = 18230792 | doi = 10.1093/jnci/djm328 }}</ref>
 
[[Sunitinib]] also inhibits Flt3.
 
[[Lestaurtinib]] is in clinical trials.
 
A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment.<ref>{{cite journal|url=http://www.nature.com/nature/journal/v485/n7397/full/nature11016.html|title=Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia|first1=Catherine C.|last1=Smith|first2=Qi|last2=Wang|first3=Chen-Shan|last3=Chin|first4=Sara|last4=Salerno|first5=Lauren E.|last5=Damon|first6=Mark J.|last6=Levis|first7=Alexander E.|last7=Perl|first8=Kevin J.|last8=Travers|first9=Susana|last9=Wang|first10=Jeremy P.|last10=Hunt|first11=Patrick P.|last11=Zarrinkar|first12=Eric E.|last12=Schadt|first13=Andrew|last13=Kasarskis|first14=John|last14=Kuriyan|first15=Neil P.|last15=Shah|date=15 April 2012|journal=Nature|volume=485|issue=7397|pages=260–263|doi=10.1038/nature11016|pmid=22504184|pmc=3390926}}</ref>
 
== See also ==
{{Div col}}
* [[Cluster of differentiation]]
* [[Cluster of differentiation]]
* [[cytokine receptor]]
* [[cytokine receptor]]
Line 82: Line 53:
* [[oncogene]]
* [[oncogene]]
* [[hematopoiesis]]
* [[hematopoiesis]]
* [[Lymphopoiesis#Labeling lymphopoiesis]]
{{Div col end}}


==References==
== References ==
<references />
{{Reflist|35em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
*{{cite journal  | vauthors=Masson K, Rönnstrand L |title=Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3. |journal=[[Cell. Signal.]] |volume=21 |issue= 12 |pages= 1717–1726 |year= 2009 |pmid= 19540337 |doi=10.1016/j.cellsig.2009.06.002  |url=http://lup.lub.lu.se/record/1434088 |type=Submitted manuscript }}
| citations =  
*{{cite journal  | author=Reilly JT |title=FLT3 and its role in the pathogenesis of acute myeloid leukaemia. |journal=[[Leuk. Lymphoma]] |volume=44 |issue= 1 |pages= 1–7 |year= 2003 |pmid= 12691136 |doi=10.1080/1042819021000040233 }}
*{{cite journal  | author=Reilly JT |title=FLT3 and its role in the pathogenesis of acute myeloid leukaemia. |journal=Leuk. Lymphoma |volume=44 |issue= 1 |pages= 1-7 |year= 2003 |pmid= 12691136 |doi=  }}
*{{cite journal  | vauthors=Kottaridis PD, Gale RE, Linch DC |title=Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia. |journal=Leuk. Lymphoma |volume=44 |issue= 6 |pages= 905–13 |year= 2003 |pmid= 12854887 |doi=10.1080/1042819031000067503 }}
*{{cite journal  | author=Kottaridis PD, Gale RE, Linch DC |title=Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia. |journal=Leuk. Lymphoma |volume=44 |issue= 6 |pages= 905-13 |year= 2003 |pmid= 12854887 |doi=  }}
*{{cite journal  | author=Gilliland DG |title=FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors. |journal=Best Practice & Research. Clinical Haematology |volume=16 |issue= 3 |pages= 409–17 |year= 2004 |pmid= 12935959 |doi=10.1016/S1521-6926(03)00063-X }}
*{{cite journal  | author=Gilliland DG |title=FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors. |journal=Best practice & research. Clinical haematology |volume=16 |issue= 3 |pages= 409-17 |year= 2004 |pmid= 12935959 |doi=  }}
*{{cite journal  | vauthors=Drexler HG, Quentmeier H |title=FLT3: receptor and ligand. |journal=[[Growth Factors (journal)|Growth Factors]] |volume=22 |issue= 2 |pages= 71–3 |year= 2005 |pmid= 15253381 |doi=10.1080/08977190410001700989 }}
*{{cite journal  | author=Drexler HG, Quentmeier H |title=FLT3: receptor and ligand. |journal=Growth Factors |volume=22 |issue= 2 |pages= 71-3 |year= 2005 |pmid= 15253381 |doi=  }}
*{{cite journal  | vauthors=Naoe T, Kiyoi H |title=Normal and oncogenic FLT3. |journal=[[Cell. Mol. Life Sci.]] |volume=61 |issue= 23 |pages= 2932–8 |year= 2005 |pmid= 15583855 |doi= 10.1007/s00018-004-4274-x }}
*{{cite journal  | author=Naoe T, Kiyoi H |title=Normal and oncogenic FLT3. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 23 |pages= 2932-8 |year= 2005 |pmid= 15583855 |doi= 10.1007/s00018-004-4274-x }}
*{{cite journal  | vauthors=Sternberg DW, Licht JD |title=Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges. |journal=Curr. Opin. Hematol. |volume=12 |issue= 1 |pages= 7–13 |year= 2005 |pmid= 15604885 |doi=10.1097/01.moh.0000147891.06584.d7 }}
*{{cite journal  | author=Sternberg DW, Licht JD |title=Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges. |journal=Curr. Opin. Hematol. |volume=12 |issue= 1 |pages= 7-13 |year= 2005 |pmid= 15604885 |doi=  }}
*{{cite journal  | vauthors=Marcucci G, Mrózek K, Bloomfield CD |title=Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. |journal=Curr. Opin. Hematol. |volume=12 |issue= 1 |pages= 68–75 |year= 2005 |pmid= 15604894 |doi=10.1097/01.moh.0000149608.29685.d1 }}
*{{cite journal  | author=Marcucci G, Mrózek K, Bloomfield CD |title=Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. |journal=Curr. Opin. Hematol. |volume=12 |issue= 1 |pages= 68-75 |year= 2005 |pmid= 15604894 |doi=  }}
*{{cite journal  | vauthors=Markovic A, MacKenzie KL, Lock RB |title=FLT-3: a new focus in the understanding of acute leukemia. |journal=[[Int. J. Biochem. Cell Biol.]] |volume=37 |issue= 6 |pages= 1168–72 |year= 2005 |pmid= 15778081 |doi= 10.1016/j.biocel.2004.12.005 }}
*{{cite journal  | author=Markovic A, MacKenzie KL, Lock RB |title=FLT-3: a new focus in the understanding of acute leukemia. |journal=Int. J. Biochem. Cell Biol. |volume=37 |issue= 6 |pages= 1168-72 |year= 2005 |pmid= 15778081 |doi= 10.1016/j.biocel.2004.12.005 }}
*{{cite journal  | vauthors=Zheng R, Small D |title=Mutant FLT3 signaling contributes to a block in myeloid differentiation. |journal=Leuk. Lymphoma |volume=46 |issue= 12 |pages= 1679–87 |year= 2006 |pmid= 16263569 |doi= 10.1080/10428190500261740 }}
*{{cite journal  | author=Zheng R, Small D |title=Mutant FLT3 signaling contributes to a block in myeloid differentiation. |journal=Leuk. Lymphoma |volume=46 |issue= 12 |pages= 1679-87 |year= 2006 |pmid= 16263569 |doi= 10.1080/10428190500261740 }}
*{{cite journal  | vauthors=Parcells BW, Ikeda AK, Simms-Waldrip T |title=FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. |journal=Stem Cells |volume=24 |issue= 5 |pages= 1174–84 |year= 2007 |pmid= 16410383 |doi= 10.1634/stemcells.2005-0519 |display-authors=etal}}
*{{cite journal  | author=Parcells BW, Ikeda AK, Simms-Waldrip T, ''et al.'' |title=FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. |journal=Stem Cells |volume=24 |issue= 5 |pages= 1174-84 |year= 2007 |pmid= 16410383 |doi= 10.1634/stemcells.2005-0519 }}
*{{cite journal  | vauthors=Stubbs MC, Armstrong SA |title=FLT3 as a therapeutic target in childhood acute leukemia. |journal=Current Drug Targets |volume=8 |issue= 6 |pages= 703–14 |year= 2007 |pmid= 17584026 |doi=10.2174/138945007780830782 }}
*{{cite journal  | author=Stubbs MC, Armstrong SA |title=FLT3 as a therapeutic target in childhood acute leukemia. |journal=Current drug targets |volume=8 |issue= 6 |pages= 703-14 |year= 2007 |pmid= 17584026 |doi=  }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|CD135+Antigen}}
* {{MeshName|CD135+Antigen}}
* {{UCSC gene info|FLT3}}


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{{Oncogenes}}
{{Oncogenes}}
{{SIB}}
{{Tyrosine kinases}}
{{Enzymes}}
{{Cytokine receptor modulators}}
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[[Category:Tyrosine kinases]]
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Latest revision as of 11:29, 9 January 2019

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Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

It is expressed on the surface of many hematopoietic progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.

The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML).[1] High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.

Structure

FLT3 is composed of five extracellular immunoglobulin-like domains, an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane.[2]

Function

CD135 is a Class III receptor tyrosine kinase. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L.[3] The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development, but not for the development of other blood cells (myeloid development).

Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:

TGF-Beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.[2]

Clinical significance

Cell surface marker

Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) express high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive.[citation needed] (See Lymphopoiesis#Labeling lymphopoiesis)

Role in cancer

CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.[4] Mutations of the FLT3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with acute myelogenous leukemia (AML) and are a prognostic indicator associated with adverse disease outcome.

FLT3 inhibitors

Gilteritinib, a dual FLT3-AXL tyrosine kinase inhibitor is currently in multiple Phase III trials in acute myeloid leukemia (AML).[5] In 2017, gilteritinib gained FDA orphan drug status for AML.[6]

Quizartinib (AC220) had good results in a phase II clinical trial for AML patients with FLT3 mutations.[7] for refractory AML – particularly in patients who went on to have a stem cell transplant.[8]

Midostaurin was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.[9] The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

Sorafenib has been reported to show significant activity against Flt3-ITD positive acute myelogenous leukemia.[10][11]

Sunitinib also inhibits Flt3.

Lestaurtinib is in clinical trials.

A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment.[12]

See also

References

  1. ↑ Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (April 2001). "Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies". Blood. 97 (8): 2434–9. doi:10.1182/blood.V97.8.2434. PMID 11290608.
  2. ↑ 2.0 2.1 "FLT3 Signaling". Pathway Central. SABiosciences.
  3. ↑ Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN (February 2011). "Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex". Blood. 118 (1): 60–68. doi:10.1182/blood-2011-01-329532. PMID 21389326.
  4. ↑ Huret J-L. "FLT3 (FMS-like tyrosine kinase 3)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. University Hospital of Poitiers.
  5. ↑ https://clinicaltrials.gov/ct2/results?cond=&term=&type=&rslt=&age_v=&gndr=&intr=Gilteritinib&titles=&outc=&spons=&lead=&id=&cntry=&state=&city=&dist=&locn=&phase=2&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&lupd_s=&lupd_e=. Missing or empty |title= (help)
  6. ↑ "Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia". 20 July 2017.
  7. ↑ "Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)". ClinicalTrials.gov. U.S. National Institutes of Health.
  8. ↑ Gever J (2012-12-09). "Drug Tames Refractory AML". ASH: Hematology Latest News. MedPage Today, LLC.
  9. ↑ Commissioner, Office of the. "Press Announcements - FDA approves new combination treatment for acute myeloid leukemia". www.fda.gov. Retrieved 2017-05-04.
  10. ↑ Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A (June 2009). "Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation". Blood. 113 (26): 6567–71. doi:10.1182/blood-2009-03-208298. PMID 19389879.
  11. ↑ Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, Estrov Z, Quintás-Cardama A, Small D, Cortes J, Andreeff M (February 2008). "Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia". J. Natl. Cancer Inst. 100 (3): 184–98. doi:10.1093/jnci/djm328. PMID 18230792.
  12. ↑ Smith, Catherine C.; Wang, Qi; Chin, Chen-Shan; Salerno, Sara; Damon, Lauren E.; Levis, Mark J.; Perl, Alexander E.; Travers, Kevin J.; Wang, Susana; Hunt, Jeremy P.; Zarrinkar, Patrick P.; Schadt, Eric E.; Kasarskis, Andrew; Kuriyan, John; Shah, Neil P. (15 April 2012). "Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia". Nature. 485 (7397): 260–263. doi:10.1038/nature11016. PMC 3390926. PMID 22504184.

Further reading

External links

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