Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML

Heidel, Florian H., Bullinger, Lars, Feng, Zhaohui, Wang, Zhu, Neff, Tobias A., Stein, Lauren, Kalaitzidis, Demetrios, Lane, Steve W. and Armstrong, Scott A. (2012) Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell, 10 4: 412-424. doi:10.1016/j.stem.2012.02.017


Author Heidel, Florian H.
Bullinger, Lars
Feng, Zhaohui
Wang, Zhu
Neff, Tobias A.
Stein, Lauren
Kalaitzidis, Demetrios
Lane, Steve W.
Armstrong, Scott A.
Title Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML
Formatted title
Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML
Journal name Cell Stem Cell   Check publisher's open access policy
ISSN 1934-5909
1875-9777
Publication date 2012-04-01
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.stem.2012.02.017
Open Access Status Not Open Access
Volume 10
Issue 4
Start page 412
End page 424
Total pages 13
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Abstract Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
Formatted abstract
A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of β-catenin during fetal HSC development leads to impairment of self-renewal while β-catenin is dispensable in fully developed adult HSCs. Whether β-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of β-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of β-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of β-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces β-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting β-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.
Keyword Hematopoietic stem cells
HSC
Leukemia stem cells
LSC
CML
Imatinib
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 14-1069
MR/M010392/1
P30 CA006516
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
 
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