Gopalakrishnapillai Anilkumar, Kolb E Anders, Dhanan Priyanka, Mason Robert W, Napper Andrew, Barwe Sonali P
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, United States of America.
PLoS One. 2015 Oct 14;10(10):e0140564. doi: 10.1371/journal.pone.0140564. eCollection 2015.
The bone marrow microenvironment plays an important role in acute lymphoblastic leukemia (ALL) cell proliferation, maintenance, and resistance to chemotherapy. Annexin II (ANX2) is abundantly expressed on bone marrow cells and complexes with p11 to form ANX2/p11-hetero-tetramer (ANX2T). We present evidence that p11 is upregulated in refractory ALL cell lines and patient samples. A small molecule inhibitor that disrupts ANX2/p11 interaction (ANX2T inhibitor), an anti-ANX2 antibody, and knockdown of p11, abrogated ALL cell adhesion to osteoblasts, indicating that ANX2/p11 interaction facilitates binding and retention of ALL cells in the bone marrow. Furthermore, ANX2T inhibitor increased the sensitivity of primary ALL cells co-cultured with osteoblasts to dexamethasone and vincristine induced cell death. Finally, in an orthotopic leukemia xenograft mouse model, the number of ALL cells homing to the bone marrow was reduced by 40-50% in mice injected with anti-ANX2 antibody, anti-p11 antibody or ANX2T inhibitor compared to respective controls. In a long-term engraftment assay, the percentage of ALL cells in mouse blood, bone marrow and spleen was reduced in mice treated with agents that disrupt ANX2/p11 interaction. These data show that disruption of ANX2/p11 interaction results in reduced ALL cell adhesion to osteoblasts, increased ALL cell sensitization to chemotherapy, and suppression of ALL cell homing and engraftment.
骨髓微环境在急性淋巴细胞白血病（ALL）细胞增殖、维持及化疗耐药中发挥重要作用。膜联蛋白II（ANX2）在骨髓细胞上大量表达，并与p11形成复合物，构成ANX2/p11异源四聚体（ANX2T）。我们提供的证据表明，p11在难治性ALL细胞系和患者样本中上调。一种破坏ANX2/p11相互作用的小分子抑制剂（ANX2T抑制剂）、抗ANX2抗体以及p11基因敲低，均消除了ALL细胞与成骨细胞的黏附，表明ANX2/p11相互作用促进ALL细胞在骨髓中的结合与滞留。此外，ANX2T抑制剂增加了与成骨细胞共培养的原代ALL细胞对地塞米松和长春新碱诱导的细胞死亡的敏感性。最后，在原位白血病异种移植小鼠模型中，与各自对照组相比，注射抗ANX2抗体、抗p11抗体或ANX2T抑制剂的小鼠归巢至骨髓的ALL细胞数量减少了40 - 50%。在长期植入试验中，用破坏ANX2/p11相互作用的药物处理的小鼠，其血液、骨髓和脾脏中ALL细胞的百分比降低。这些数据表明，破坏ANX2/p11相互作用会导致ALL细胞与成骨细胞的黏附减少、ALL细胞对化疗的敏感性增加以及ALL细胞归巢和植入受到抑制。
