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Article: Sorafenib treatment of FLT3-ITD + acute myeloid leukemia: Favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

TitleSorafenib treatment of FLT3-ITD + acute myeloid leukemia: Favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation
Authors
Issue Date2012
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2012, v. 119 n. 22, p. 5133-5143 How to Cite?
AbstractInternal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD + AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors. © 2012 by The American Society of Hematology.
Persistent Identifierhttp://hdl.handle.net/10722/146880
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395
ISI Accession Number ID
Funding AgencyGrant Number
Strategy Research Theme on Cancer Stem Cells at University of Hong Kong
Croucher Foundation
Lady Tata Memorial Trust
Funding Information:

This work was supported by a grant from the Strategy Research Theme on Cancer Stem Cells at the University of Hong Kong, donations from the S. K. Yee Medical Foundation, Lee Hysan Foundation, and Tang King Yin Research Fund, as well as the Canadian Cancer Society. A. C. was supported by the Croucher Foundation Fellowship and T. K. F. by the Lady Tata Memorial Trust. Sorafenib was provided by Bayer Health and sunitinib by Pfizer Corp.

References

 

DC FieldValueLanguage
dc.contributor.authorMan, CHen_HK
dc.contributor.authorFung, TKen_HK
dc.contributor.authorHo, Cen_HK
dc.contributor.authorHan, HHCen_HK
dc.contributor.authorChow, HCHen_HK
dc.contributor.authorMa, ACHen_HK
dc.contributor.authorChoi, WWLen_HK
dc.contributor.authorLok, Sen_HK
dc.contributor.authorCheung, AMSen_HK
dc.contributor.authorEaves, Cen_HK
dc.contributor.authorKwong, YLen_HK
dc.contributor.authorLeung, AYHen_HK
dc.date.accessioned2012-05-23T05:48:27Z-
dc.date.available2012-05-23T05:48:27Z-
dc.date.issued2012en_HK
dc.identifier.citationBlood, 2012, v. 119 n. 22, p. 5133-5143en_HK
dc.identifier.issn0006-4971en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146880-
dc.description.abstractInternal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD + AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors. © 2012 by The American Society of Hematology.en_HK
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/en_HK
dc.relation.ispartofBlooden_HK
dc.subject.meshAntineoplastic Agents - administration and dosage - adverse effects-
dc.subject.meshBenzenesulfonates - administration and dosage - adverse effects-
dc.subject.meshDrug Resistance, Neoplasm - drug effects - genetics-
dc.subject.meshGene Expression Regulation, Leukemic-
dc.subject.meshLeukemia, Myeloid, Acute - drug therapy - enzymology - genetics - pathology-
dc.titleSorafenib treatment of FLT3-ITD + acute myeloid leukemia: Favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutationen_HK
dc.typeArticleen_HK
dc.identifier.emailChoi, WWL: choiwl@hkucc.hku.hken_HK
dc.identifier.emailLok, S: silok@genome.hku.hken_HK
dc.identifier.authorityChoi, WWL=rp00247en_HK
dc.identifier.authorityLok, S=rp00271en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood-2011-06-363960en_HK
dc.identifier.pmid22368270-
dc.identifier.scopuseid_2-s2.0-84861906112en_HK
dc.identifier.hkuros199388en_US
dc.identifier.hkuros222232-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84861906112&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume119en_HK
dc.identifier.issue22en_HK
dc.identifier.spage5133en_HK
dc.identifier.epage5143en_HK
dc.identifier.eissn1528-0020-
dc.identifier.isiWOS:000305291800016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridMan, CH=55241939800en_HK
dc.identifier.scopusauthoridFung, TK=7102715924en_HK
dc.identifier.scopusauthoridHo, C=55222467600en_HK
dc.identifier.scopusauthoridHan, HHC=7401969322en_HK
dc.identifier.scopusauthoridChow, HCH=7102303391en_HK
dc.identifier.scopusauthoridMa, ACH=52664122100en_HK
dc.identifier.scopusauthoridChoi, WWL=25227295700en_HK
dc.identifier.scopusauthoridLok, S=21035019900en_HK
dc.identifier.scopusauthoridCheung, AMS=55190021400en_HK
dc.identifier.scopusauthoridEaves, C=7101806471en_HK
dc.identifier.scopusauthoridKwong, YL=55158018200en_HK
dc.identifier.scopusauthoridLeung, AYH=55091367300en_HK

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