Effects of dasatinib on Src kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells

Heiko Konig, Mhairi Copland, Su Chu, Richard Jove, Tessa L. Holyoake, Ravi Bhatia

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl-induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34+ cells and CD34+CD38- cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl-dependent and -independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl-dependent Src activity. Dasatinib inhibited P-mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti-Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients.

Original languageEnglish (US)
Pages (from-to)9624-9633
Number of pages10
JournalCancer Research
Volume68
Issue number23
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

Fingerprint

src-Family Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intercellular Signaling Peptides and Proteins
Mitogen-Activated Protein Kinases
Dasatinib
bcr-abl Fusion Proteins
Leukemia, Myeloid, Chronic Phase
Protein-Tyrosine Kinases
Phosphotransferases
Cell Culture Techniques
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effects of dasatinib on Src kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells. / Konig, Heiko; Copland, Mhairi; Chu, Su; Jove, Richard; Holyoake, Tessa L.; Bhatia, Ravi.

In: Cancer Research, Vol. 68, No. 23, 01.12.2008, p. 9624-9633.

Research output: Contribution to journalArticle

Konig, Heiko ; Copland, Mhairi ; Chu, Su ; Jove, Richard ; Holyoake, Tessa L. ; Bhatia, Ravi. / Effects of dasatinib on Src kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells. In: Cancer Research. 2008 ; Vol. 68, No. 23. pp. 9624-9633.
@article{49342d37c91a4f96b656ce9782bb1f52,
title = "Effects of dasatinib on Src kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells",
abstract = "Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl-induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34+ cells and CD34+CD38- cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl-dependent and -independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl-dependent Src activity. Dasatinib inhibited P-mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti-Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients.",
author = "Heiko Konig and Mhairi Copland and Su Chu and Richard Jove and Holyoake, {Tessa L.} and Ravi Bhatia",
year = "2008",
month = "12",
day = "1",
doi = "10.1158/0008-5472.CAN-08-1131",
language = "English (US)",
volume = "68",
pages = "9624--9633",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "23",

}

TY - JOUR

T1 - Effects of dasatinib on Src kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells

AU - Konig, Heiko

AU - Copland, Mhairi

AU - Chu, Su

AU - Jove, Richard

AU - Holyoake, Tessa L.

AU - Bhatia, Ravi

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl-induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34+ cells and CD34+CD38- cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl-dependent and -independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl-dependent Src activity. Dasatinib inhibited P-mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti-Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients.

AB - Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl-induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34+ cells and CD34+CD38- cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl-dependent and -independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl-dependent Src activity. Dasatinib inhibited P-mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti-Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients.

UR - http://www.scopus.com/inward/record.url?scp=57149097077&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57149097077&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-1131

DO - 10.1158/0008-5472.CAN-08-1131

M3 - Article

C2 - 19047139

AN - SCOPUS:57149097077

VL - 68

SP - 9624

EP - 9633

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 23

ER -