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Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.

Karvonen, Hanna; Chiron, David; Niininen, Wilhelmiina; Ek, Sara LU ; Jerkeman, Mats LU ; Moradi, Elaheh; Nykter, Matti; Heckman, Caroline A.; Kallioniemi, Olli and Murumägi , Astrid, et al. (2017) In Blood Advances 1(24). p.2257-2268
Abstract
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase–like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the... (More)
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase–like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the NF-κB pathway can antagonize ROR1-mediated apoptotic responses. High-throughput drug-sensitivity testing of MCL cells before and after ROR1 targeting revealed synergistic effects between cotargeting of ROR1 and the B-cell antigen receptor (BCR) or Bcl-2 family, underlining the high potential for ROR1-targeted therapies in overcoming MCL drug resistance. However, inhibition of the BCR pathway by targeted drugs such as ibrutinib can impair ROR1 expression and consequently ROR1-targeted treatments, underscoring the importance of inhibiting both pathways to augment cancer cell killing. Considering the central role of NF-κB pathway activation in B-cell malignancies, this study highlights key factors that can modulate ROR1-targeted treatments in hematological cancers. (Less)
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published
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Blood Advances
volume
1
issue
24
pages
2257 - 2268
publisher
American Society of Hematology
ISSN
2473-9529
DOI
10.1182/bloodadvances.2017010215
language
Swedish
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yes
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e16687bd-9c32-478d-8279-7fa16498c85f
date added to LUP
2019-02-05 19:59:35
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2019-02-12 11:53:23
@article{e16687bd-9c32-478d-8279-7fa16498c85f,
  abstract     = {Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase–like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the NF-κB pathway can antagonize ROR1-mediated apoptotic responses. High-throughput drug-sensitivity testing of MCL cells before and after ROR1 targeting revealed synergistic effects between cotargeting of ROR1 and the B-cell antigen receptor (BCR) or Bcl-2 family, underlining the high potential for ROR1-targeted therapies in overcoming MCL drug resistance. However, inhibition of the BCR pathway by targeted drugs such as ibrutinib can impair ROR1 expression and consequently ROR1-targeted treatments, underscoring the importance of inhibiting both pathways to augment cancer cell killing. Considering the central role of NF-κB pathway activation in B-cell malignancies, this study highlights key factors that can modulate ROR1-targeted treatments in hematological cancers.},
  author       = {Karvonen, Hanna and Chiron, David and Niininen, Wilhelmiina and Ek, Sara and Jerkeman, Mats and Moradi, Elaheh and Nykter, Matti and Heckman, Caroline A. and Kallioniemi, Olli and Murumägi , Astrid and Ungureanu, Daniela},
  issn         = {2473-9529},
  language     = {swe},
  month        = {11},
  number       = {24},
  pages        = {2257--2268},
  publisher    = {American Society of Hematology},
  series       = {Blood Advances},
  title        = {Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.},
  url          = {http://dx.doi.org/10.1182/bloodadvances.2017010215},
  volume       = {1},
  year         = {2017},
}