Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITDAML Journal Article
| Authors: | Sexauer, A.; Perl, A.; Yang, X.; Borowitz, M.; Gocke, C.; Rajkhowa, T.; Thiede, C.; Frattini, M.; Nybakken, G. E.; Pratz, K.; Karp, J.; Smith, B. D.; Levis, M. |
| Article Title: | Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITDAML |
| Abstract: | A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal BM responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of BM blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a preexisting C/EBPα mutation and another developed a C/EBPα mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts cocultured with human BM stroma, FLT3 inhibition with quizartinib induced cell-cycle arrest and differentiation rather than apoptosis. The present study is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the patho-genesis of AML. © 2012 by The American Society of Hematology. |
| Keywords: | adult; cancer survival; clinical article; controlled study; human tissue; aged; acute granulocytic leukemia; leukemia, myeloid, acute; cancer growth; antineoplastic agents; flow cytometry; bone marrow cells; cell cycle; apoptosis; enzyme inhibition; neoplasm proteins; in vivo study; cell differentiation; in vitro study; tumor cells, cultured; protein kinase inhibitors; neoplastic stem cells; immunoblotting; stroma; cell cycle arrest; gene duplication; inhibition kinetics; neutrophils; bone marrow cell; flt3 ligand; clinical trials, phase ii as topic; stromal cells; multicenter studies as topic; coculture; coculture techniques; blast cell; myelopoiesis; cell disruption; fms-like tyrosine kinase 3; ccaat enhancer binding protein alpha; ccaat-enhancer-binding protein-alpha; quizartinib; phenylurea compounds; benzothiazoles |
| Journal Title: | Blood |
| Volume: | 120 |
| Issue: | 20 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2012-11-15 |
| Start Page: | 4205 |
| End Page: | 4214 |
| Language: | English |
| DOI: | 10.1182/blood-2012-01-402545 |
| PROVIDER: | scopus |
| PMCID: | PMC3501718 |
| PUBMED: | 23012328 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 January 2013" - "CODEN: BLOOA" - "Source: Scopus" |
