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- Publisher Website: 10.1038/leu.2012.195
- Scopus: eid_2-s2.0-84873569249
- PMID: 22797419
- WOS: WOS:000315553600002
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Article: FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia
Title | FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia |
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Authors | |
Issue Date | 2013 |
Publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/leu |
Citation | Leukemia, 2013, v. 27 n. 2, p. 260-268 How to Cite? |
Abstract | Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome. |
Persistent Identifier | http://hdl.handle.net/10722/184572 |
ISSN | 2023 Impact Factor: 12.8 2023 SCImago Journal Rankings: 3.662 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Leung, AYH | - |
dc.contributor.author | Man, CH | - |
dc.contributor.author | Kwong, YL | - |
dc.date.accessioned | 2013-07-15T09:56:21Z | - |
dc.date.available | 2013-07-15T09:56:21Z | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Leukemia, 2013, v. 27 n. 2, p. 260-268 | - |
dc.identifier.issn | 0887-6924 | - |
dc.identifier.uri | http://hdl.handle.net/10722/184572 | - |
dc.description.abstract | Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome. | - |
dc.language | eng | - |
dc.publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/leu | - |
dc.relation.ispartof | Leukemia | - |
dc.title | FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia | - |
dc.type | Article | - |
dc.identifier.email | Leung, AYH: ayhleung@hku.hk | - |
dc.identifier.email | Man, CH: csman729@hku.hk | - |
dc.identifier.email | Kwong, YL: ylkwong@hku.hk | - |
dc.identifier.authority | Leung, AYH=rp00265 | - |
dc.identifier.authority | Man, CH=rp02543 | - |
dc.identifier.authority | Kwong, YL=rp00358 | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1038/leu.2012.195 | - |
dc.identifier.pmid | 22797419 | - |
dc.identifier.scopus | eid_2-s2.0-84873569249 | - |
dc.identifier.hkuros | 215279 | - |
dc.identifier.volume | 27 | - |
dc.identifier.issue | 2 | - |
dc.identifier.spage | 260 | - |
dc.identifier.epage | 268 | - |
dc.identifier.isi | WOS:000315553600002 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 0887-6924 | - |