β-catenin is a candidate therapeutic target for myeloid neoplasms with del(5q)

Liping Li, Yue Sheng, Wenshu Li, Chao Hu, Nupur Mittal, Kaoru Tohyama, Amber Seba, You Yang Zhao, Howard Ozer, Tongyu Zhu, Zhijian Qian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q).

Original languageEnglish (US)
Pages (from-to)4116-4126
Number of pages11
JournalCancer Research
Volume77
Issue number15
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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