期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 10, 页码 4144-4157出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI68951
关键词
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资金
- NIH [CA095512, CA16058, CA140158, CA88932, CA95684, CA49639, HL-083187, USPHS MO1 RR08084]
- US Army CML Research Program [W81XWH-07-1-0270]
- Leukemia and Lymphoma Society Scholarship
- American-Italian Cancer Foundation
- Fonds de la Recherche en Sante du Quebec
- Danish Medical Research Council
- Danish Cancer Society
- Karen Elise Jensen Foundation
- Alex's Lemonade Stand
- Cancer Research UK [C11074/A11008]
- [SCOR 7004-11]
- National Institute for Health Research [NF-SI-0611-10275] Funding Source: researchfish
The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression - but not activity - of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/beta-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and beta-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/beta-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and. relieve lifelong patient dependence on TKIs.
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