Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Shimadzu Corporation, Tokyo, Japan.
Exp Hematol. 2021 Feb;94:31-36. doi: 10.1016/j.exphem.2020.12.003. Epub 2021 Jan 14.
BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells. We found that BAALC physically interacts with DBN1, which is an actin-binding protein and promotes cell adhesion and mobility by forming cell membrane spines during cell-cell interactions. Drebrin1 downregulation impeded cell adhesion to bone marrow stromal cells, resulting in improvement of sensitivity to cytarabine. Taken together, our findings suggest that BAALC-DBN1 interaction contributes to the anchoring of BAALC-expressing cells in the bone marrow, which in turn leads to resistance to cytotoxic drugs. Therefore, the BAALC-DBN1 interaction provides us with an opportunity to overcome the chemotherapy resistance in BAALC-activated leukemia via functional blockage of these genes.
BAALC 被鉴定为一个与白血病相关的基因，在 CD34 阳性造血干细胞中高度表达。高 BAALC 表达与几种类型的急性髓系白血病的不良预后相关。我们通过质谱法探索了 BAALC 的结合蛋白伴侣，并分析了表达 BAALC 的白血病细胞的生物学特性。我们发现 BAALC 与 DBN1 发生物理相互作用，DBN1 是一种肌动蛋白结合蛋白，通过在细胞-细胞相互作用期间形成细胞膜脊促进细胞黏附和迁移。Drebrin1 的下调阻碍了细胞与骨髓基质细胞的黏附，从而提高了对阿糖胞苷的敏感性。总之，我们的研究结果表明，BAALC-DBN1 相互作用有助于表达 BAALC 的细胞在骨髓中的锚定，进而导致对细胞毒药物的耐药性。因此，BAALC-DBN1 相互作用为我们提供了一个机会，通过功能阻断这些基因来克服 BAALC 激活的白血病中的化疗耐药性。
