Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

Paavo O. Pietarinen, Christopher A. Eide, Pilar Ayuda-Durán, Swapnil Potdar, Heikki Kuusanmäki, Emma I. Andersson, John P. Mpindi, Tea Pemovska, Mika Kontro, Caroline A. Heckman, Olli Kallioniemi, Krister Wennerberg, Henrik Hjorth-Hansen, Brian Druker, Jorrit M. Enserink, Jeffrey Tyner, Satu Mustjoki, Kimmo Porkka

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1- positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1- positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34- negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.

Original languageEnglish (US)
Pages (from-to)22606-22615
Number of pages10
JournalOncotarget
Volume8
Issue number14
DOIs
StatePublished - 2017

Fingerprint

Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Leukemia
Stem Cells
Leukemia, Myeloid, Chronic Phase
Blast Crisis
Philadelphia Chromosome
Drug Discovery
Therapeutics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Resistance
Cell Differentiation
Cell Survival
Cohort Studies
Pharmaceutical Preparations
Population

Keywords

  • CD34
  • Chronic myeloid leukemia
  • Ex vivo
  • High-throughput drug screening
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology

Cite this

Pietarinen, P. O., Eide, C. A., Ayuda-Durán, P., Potdar, S., Kuusanmäki, H., Andersson, E. I., ... Porkka, K. (2017). Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors. Oncotarget, 8(14), 22606-22615. https://doi.org/10.18632/oncotarget.15146

Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors. / Pietarinen, Paavo O.; Eide, Christopher A.; Ayuda-Durán, Pilar; Potdar, Swapnil; Kuusanmäki, Heikki; Andersson, Emma I.; Mpindi, John P.; Pemovska, Tea; Kontro, Mika; Heckman, Caroline A.; Kallioniemi, Olli; Wennerberg, Krister; Hjorth-Hansen, Henrik; Druker, Brian; Enserink, Jorrit M.; Tyner, Jeffrey; Mustjoki, Satu; Porkka, Kimmo.

In: Oncotarget, Vol. 8, No. 14, 2017, p. 22606-22615.

Research output: Contribution to journalArticle

Pietarinen, PO, Eide, CA, Ayuda-Durán, P, Potdar, S, Kuusanmäki, H, Andersson, EI, Mpindi, JP, Pemovska, T, Kontro, M, Heckman, CA, Kallioniemi, O, Wennerberg, K, Hjorth-Hansen, H, Druker, B, Enserink, JM, Tyner, J, Mustjoki, S & Porkka, K 2017, 'Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors', Oncotarget, vol. 8, no. 14, pp. 22606-22615. https://doi.org/10.18632/oncotarget.15146
Pietarinen PO, Eide CA, Ayuda-Durán P, Potdar S, Kuusanmäki H, Andersson EI et al. Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors. Oncotarget. 2017;8(14):22606-22615. https://doi.org/10.18632/oncotarget.15146
Pietarinen, Paavo O. ; Eide, Christopher A. ; Ayuda-Durán, Pilar ; Potdar, Swapnil ; Kuusanmäki, Heikki ; Andersson, Emma I. ; Mpindi, John P. ; Pemovska, Tea ; Kontro, Mika ; Heckman, Caroline A. ; Kallioniemi, Olli ; Wennerberg, Krister ; Hjorth-Hansen, Henrik ; Druker, Brian ; Enserink, Jorrit M. ; Tyner, Jeffrey ; Mustjoki, Satu ; Porkka, Kimmo. / Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors. In: Oncotarget. 2017 ; Vol. 8, No. 14. pp. 22606-22615.
@article{8eeca6fdd8d14d6bb3d6de51debe70c4,
title = "Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors",
abstract = "Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1- positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1- positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34- negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.",
keywords = "CD34, Chronic myeloid leukemia, Ex vivo, High-throughput drug screening, Tyrosine kinase inhibitors",
author = "Pietarinen, {Paavo O.} and Eide, {Christopher A.} and Pilar Ayuda-Dur{\'a}n and Swapnil Potdar and Heikki Kuusanm{\"a}ki and Andersson, {Emma I.} and Mpindi, {John P.} and Tea Pemovska and Mika Kontro and Heckman, {Caroline A.} and Olli Kallioniemi and Krister Wennerberg and Henrik Hjorth-Hansen and Brian Druker and Enserink, {Jorrit M.} and Jeffrey Tyner and Satu Mustjoki and Kimmo Porkka",
year = "2017",
doi = "10.18632/oncotarget.15146",
language = "English (US)",
volume = "8",
pages = "22606--22615",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "14",

}

TY - JOUR

T1 - Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

AU - Pietarinen, Paavo O.

AU - Eide, Christopher A.

AU - Ayuda-Durán, Pilar

AU - Potdar, Swapnil

AU - Kuusanmäki, Heikki

AU - Andersson, Emma I.

AU - Mpindi, John P.

AU - Pemovska, Tea

AU - Kontro, Mika

AU - Heckman, Caroline A.

AU - Kallioniemi, Olli

AU - Wennerberg, Krister

AU - Hjorth-Hansen, Henrik

AU - Druker, Brian

AU - Enserink, Jorrit M.

AU - Tyner, Jeffrey

AU - Mustjoki, Satu

AU - Porkka, Kimmo

PY - 2017

Y1 - 2017

N2 - Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1- positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1- positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34- negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.

AB - Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1- positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1- positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34- negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.

KW - CD34

KW - Chronic myeloid leukemia

KW - Ex vivo

KW - High-throughput drug screening

KW - Tyrosine kinase inhibitors

UR - http://www.scopus.com/inward/record.url?scp=85016937033&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016937033&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.15146

DO - 10.18632/oncotarget.15146

M3 - Article

VL - 8

SP - 22606

EP - 22615

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 14

ER -