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Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases

By Lina Han, Jan Jacob Schuringa, André Mulder and Edo Vellenga

Abstract

A number of signaling pathways might be frequently disrupted in acute myeloid leukemia (AML). We questioned whether the dual SRC/ABL kinase inhibitor dasatinib can affect AML cells and whether differences can be observed with normal CD34+ cells. First, we demonstrated that normal cord blood (CB) CD34+ cells were unaffected by dasatinib at a low concentration (0.5 nM) in the long-term culture on MS5 stromal cells. No changes were observed in proliferation, differentiation, and colony formation. In a subset of AML cases (3/15), a distinct reduction in cell proliferation was observed, ranging from 48% to 91% inhibition at 0.5 nM of dasatinib, in particular, those characterized by BCR–ABL or KIT mutations. Moreover, the inhibitory effects of dasatinib were cytokine specific. Stem cell factor-mediated proliferation was significantly impaired, associated with a reduced phosphorylation of ERK1/2 and STAT5, whereas no effect was observed on interleukin-3 and thrombopoietin-mediated signaling despite SRC activation. In conclusion, this study demonstrates that dasatinib is a potential inhibitor in a subgroup of AML, especially those that express BCR–ABL or KIT mutations

Topics: Original Article
Publisher: Springer-Verlag
OAI identifier: oai:pubmedcentral.nih.gov:2908401
Provided by: PubMed Central

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Citations

  1. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.
  2. (2008). A critical role for Lyn in acute myeloid leukemia.
  3. (2005). Abl inhibitor BMS354825 binding mode in Abelson kinase revealed by molecular docking studies.
  4. (2006). Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t (8;21): a Cancer and Leukemia Group B Study.
  5. (2007). Arcaro A
  6. (2003). BCR–ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.
  7. (2000). C-kit mutations in core binding factor leukemias.
  8. (2009). Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT
  9. (2006). Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells.
  10. (2007). Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells.
  11. (2006). Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.
  12. (2008). Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells. Exp Hematol 36:655–666
  13. (2005). Detection of an activating c-kit mutation by real-time PCR in patients with anaphylaxis.
  14. (2004). Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/ Abl kinase inhibitor with potent antitumor activity in preclinical assays.
  15. (2007). Establishing long-term cultures with selfrenewing acute myeloid leukemia stem/progenitor cells. Exp Hematol 35:1538–1549
  16. (1995). Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression.
  17. (2009). Ex vivo assays to study selfrenewal and long-term expansion of genetically modified primary human acute myeloid leukemia stem cells.
  18. (2002). Genetics of myeloid leukemias.
  19. (2006). Holyoake TL
  20. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
  21. (2007). Identification and functional signature of genes regulated by structurally different ABL kinase inhibitors.
  22. (2008). Increased C-kit intensity is a poor prognostic factor for progression-free and overall survival in patients with newly diagnosed AML.
  23. (2008). Initial testing of dasatinib by the pediatric preclinical testing program.
  24. (1997). Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines.
  25. (2002). JAKs, STATs and Src kinases in hematopoiesis.
  26. (2004). KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication.
  27. (2008). Kit regulates maintenance of quiescent hematopoietic stem cells.
  28. (2007). Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction.
  29. (2007). Lyn is an important component of the signal transduction pathway specific to FLT3/ ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD. Leukemia
  30. (2004). Mechanisms of transformation by the BCR– ABL oncogene: new perspectives in the post-imatinib era. Leuk Res 28(Suppl 1):S21–S28
  31. (2007). MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
  32. (2008). Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway.
  33. (2005). Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations. Exp Hematol 33:469–479
  34. (2004). The interplay between Src family kinases and receptor tyrosine kinases.
  35. (1998). The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL).
  36. (2006). The role of Src in solid and hematologic malignancies: development of newgeneration Src inhibitors.
  37. (2008). Two cell lines of t(8;21) acute myeloid leukemia with activating KIT exon 17 mutation: models for the ‘second hit’ hypothesis.