Dasatinib targets chronic myeloid leukemia-CD34⁺ progenitors as effectively as it targets mature cells

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dc.contributor.authorHiwase, D.
dc.contributor.authorSaunders, V.
dc.contributor.authorNievergall, E.
dc.contributor.authorRoss, D.
dc.contributor.authorWhite, D.
dc.contributor.authorHughes, T.
dc.date.issued2013
dc.description.abstractDasatinib is effective in most chronic phase chronic myeloid leukemia patients both in first-line therapy and following imatinib failure. While imatinib uptake into CD34(+) cells is low compared to mononuclear cells, few data evaluate how well dasatinib targets primitive CML cells. This study compares intracellular concentration of dasatinib and Bcr-Abl kinase inhibition in CML-CD34(+) progenitors and mononuclear cells induced by dasatinib. The intracellular concentrations of dasatinib were similar between CML-CD34(+) and mononuclear cells (P=0.8). Similarly, there was no significant difference in the degree of dasatinib-mediated Bcr-Abl kinase inhibition. ABCB1 (MDR1) and ABCG2 inhibitors neither increased dasatinib intracellular concentration nor enhanced dasatinib-mediated Bcr-Abl kinase inhibition. In contrast to nilotinib, we show that dasatinib is not an ABCB1 inhibitor. Thus, dasatinib targets CML-CD34(+) progenitors as effectively as it targets mononuclear cells. ABCB1 and ABCG2 efflux pumps do not appear to influence the intracellular dasatinib concentration in CML-CD34(+) progenitors.
dc.description.statementofresponsibilityDevendra K. Hiwase, Verity A. Saunders, Eva Nievergall, Douglas D. Ross, Deborah L. White, and Timothy P. Hughes
dc.identifier.citationHaematologica: the hematology journal, 2013; 98(6):896-900
dc.identifier.doi10.3324/haematol.2012.070268
dc.identifier.issn0390-6078
dc.identifier.issn1592-8721
dc.identifier.orcidHiwase, D. [0000-0002-6666-3056]
dc.identifier.orcidWhite, D. [0000-0003-4844-333X]
dc.identifier.orcidHughes, T. [0000-0002-0910-3730] [0000-0002-7990-4509]
dc.identifier.urihttp://hdl.handle.net/2440/79010
dc.language.isoen
dc.publisherFerrata Storti Foundation
dc.rights©2013 Ferrata Storti Foundation
dc.source.urihttps://doi.org/10.3324/haematol.2012.070268
dc.subjectLeukocytes, Mononuclear
dc.subjectCells, Cultured
dc.subjectHumans
dc.subjectPyrimidines
dc.subjectThiazoles
dc.subjectATP-Binding Cassette Transporters
dc.subjectNeoplasm Proteins
dc.subjectFusion Proteins, bcr-abl
dc.subjectAntineoplastic Agents
dc.subjectAntigens, CD34
dc.subjectProtein Kinase Inhibitors
dc.subjectSubstrate Specificity
dc.subjectNeoplastic Stem Cells
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectDasatinib
dc.subjectATP Binding Cassette Transporter, Subfamily G, Member 2
dc.subjectATP Binding Cassette Transporter, Subfamily B
dc.subjectATP Binding Cassette Transporter, Subfamily B, Member 1
dc.titleDasatinib targets chronic myeloid leukemia-CD34⁺ progenitors as effectively as it targets mature cells
dc.title.alternativeDasatinib targets chronic myeloid leukemia-CD34(+) progenitors as effectively as it targets mature cells
dc.typeJournal article
pubs.publication-statusPublished

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