Publications by authors named "Yinsha Miao"

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RAG enhances BCR-ABL1-positive leukemic cell growth through its endonuclease activity in vitro and in vivo.

Cancer Sci 2021 May 4. Epub 2021 May 4.

Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.

BCR-ABL1 gene fusion associated with additional DNA lesions involves the pathogenesis of chronic myelogenous leukemia (CML) from a chronic phase (CP) to a blast crisis of B lymphoid (CML-LBC) lineage and BCR-ABL1 acute lymphoblastic leukemia (BCR-ABL1 ALL). The recombination-activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML-LBC and BCR-ABL1 ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild-type (WT) RAG and catalytically inactive RAG-expressing BCR-ABL1 and BCR-ABL1 cell lines, respectively, and demonstrate that BCR-ABL1 specifically collaborates with RAG recombinase to promote cell survival in vitro and in xenograft mice models. WT RAG-expressing BCR-ABL1 cell lines and primary CD34 bone marrow cells from CML-LBC samples maintain more double-strand breaks (DSB) compared to catalytically inactive RAG-expressing BCR-ABL1 cell lines and RAG-deficient CML-CP samples, which are measured by γ-H2AX. WT RAG-expressing BCR-ABL1 cells are biased to repair RAG-mediated DSB by the alternative non-homologous end joining pathway (a-NHEJ), which could contribute genomic instability through increasing the expression of a-NHEJ-related MRE11 and RAD50 proteins. As a result, RAG-expressing BCR-ABL1 cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR-ABL1 signaling but independent of the levels of BCR-ABL1 expression and mutations in the BCR-ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in BCR-ABL1 leukemia through its endonuclease activity.
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May 2021