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| Status |
Public on Feb 18, 2012 |
| Title |
Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with a D835 mutation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% acute myeloid leukemias (AML) 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 (BM) 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. Four pairs patients (before sorafenib treatment and after sorafenib relapse), total eight samples from four patients at the two time-points were subjected to microarray analysis. Gene expression profiling showed that leukemia cells which have become sorafenib resistant expressed a number of genes including ALDH1A1, JAK3 and MMP15, whose functions were unknown in AML. NOD/SCID mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain (TKD) mutations at D835 were identified in leukemia initiating cells (LIC) from samples before sorafenib treatment. LIC bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggested 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.
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| Overall design |
RNA from CD33+CD34+ myeloblasts at pre-sorafenib-treatment and post-sorafenib-relapse were collected and subjected to microarray analysis
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| Contributor(s) |
Man C, Fung T, Anskar LY |
| Citation(s) |
22368270 |
| Submission date |
Feb 17, 2012 |
| Last update date |
Jul 26, 2018 |
| Contact name |
Cheuk Him Man |
| E-mail(s) |
csman2021@yahoo.com.hk
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| Organization name |
HKU
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| Street address |
L816, LAB BLK, FMB, HKU
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| City |
Hong Kong |
| ZIP/Postal code |
0000 |
| Country |
Hong Kong |
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| Platforms (1) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA152007 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE35907_RAW.tar |
35.9 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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