Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors

Leukemia
D K HiwaseT P Hughes

Abstract

In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These...Continue Reading

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Citations

Aug 15, 2013·Journal of Cancer Research and Clinical Oncology·Andreas Hochhaus, Hagop Kantarjian
Mar 29, 2013·Cytokine & Growth Factor Reviews·Timothy R HercusAngel F Lopez
Feb 9, 2011·Leukemia & Lymphoma·Joana M Diamond, Junia V Melo
Jan 20, 2012·Growth Factors·Timothy R HercusAngel F Lopez
Jun 15, 2011·Expert Review of Hematology·Devendra K HiwaseDeborah L White
Feb 26, 2016·Cell Communication and Signaling : CCS·Sebastian HalbachTilman Brummer
Apr 24, 2012·Current Opinion in Structural Biology·Sophie E BroughtonMichael W Parker
Feb 14, 2012·Blood Cells, Molecules & Diseases·Mohsin ShahHeather Jørgensen
Nov 8, 2011·Hematology/oncology Clinics of North America·Paolo GallipoliTessa L Holyoake
Jun 12, 2010·IUBMB Life·Angel F LopezMichael W Parker
Jul 19, 2017·Cold Spring Harbor Perspectives in Biology·Timothy R HercusAngel F Lopez
Oct 22, 2014·Oncotarget·Angelika BergerRichard Moriggl
Dec 24, 2013·Cancer Discovery·Jennifer AsmussenNeil P Shah
Jun 3, 2021·Bioengineering·Geoffrey Brown

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis