beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells (Cancer Cell, 2010, 18:606-618)

報告日期: 2011/03/04
報告時間: 16:00/16:50
報告學生: 盧佳杏 (英文報告)
講評老師: 陳炳焜

Full Text:

β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells
Jenny Yeung, et al.Cancer Cell 18, 606-618, 2010
Speaker : Chia-Sing Lu
Commentator : Dr. Ben-Kuen Chen
Date: 20110304
Tissue specific cancer stem cells (CSCs) have been isolated from clinical samples and their self-renewal and differentiation capacity have been defined. Accumulating evidence shows that that CSCs cause tumor recurrence and drug resistance. Acute myeloid leukemia (AML) is the most common and lethal acute leukemia in adults. Previous studies have shown that Mixed Lineage Leukemia (MLL) gene fusion is the major contribution of AML by converting normal hematopoietic stem cells (HSCs) into pre-Leukemia stem cells (pre-LSCs). Though the leukemia initiating cells have been isolated from clinical samples, very little is known about the mechanisms responsible for the establishment of LSCs.
To molecularly dissect and compare the cell populations enriched in MLL pre-LSCs and LSCs of murine Leukemogenic model system and then block the pathway to determine the functional significance in leukemogenesis.
By MLL Leukemic animal model, the author successfully dissected the populations of pre-LSCs and LSCs. Higher proliferation rate and less cytokine dependence are found in LSCs than pre-LSC-enriched population. According to global expression analysis, the components of Wnt signal were activated in MLL LSC-enriched populations.
Western blot and immunofluorescence analysis indicated that β-catenin is not overexpressed but accumulated in the nucleus. In contrast, knockdown of β-catenin diminished the in vitro cloning efficiency of murine LSCs and human leukemic cells. Moreover, knockdown ofβ-catenin significantly compromised the leukemogenic potential of MLL LSCs after transplantation.
At last, the presence of potentially counteracting pathways in LSCs allows resistance toward GSK3 inhibitors. However, the Li2CO3 diet delayed the disease latency for mice transplanted with the MLL LSC-enriched population expressing the β-catenin shRNA.
Conclusions :
A highly conserved and stable requirement of β-catenin for MLL leukemic cells is implicated in disease latency of MLL leukemia and poor response to drugs. Identifiying the essential role of β-catenin in AML lead to develop effective LSC-targeted therapy.
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