title: Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML.
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.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Florian H
authors.initials: FH
authors.lastname: Heidel
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Neff
authors.forename: Lauren
authors.initials: L
authors.lastname: Stein
authors.forename: Demetrios
authors.initials: D
authors.lastname: Kalaitzidis
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D000068877:Imatinib Mesylate; D007213:Indomethacin / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; D010879:Piperazines; D011453:Prostaglandins; D011743:Pyrimidines; D051176:beta Catenin; D000068877:Imatinib Mesylate; D007213:Indomethacin