Disruption of Annexin II /p11 Interaction Suppresses Leukemia Cell Binding, Homing and Engraftment, and Sensitizes the Leukemia Cells to Chemotherapy

Abstract

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.

Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

“…Further investigation is required so that this combination could be better utilized in the clinic for pediatric ALL. Cell adhesion molecules like VLA-4 (Integrin α 4 β 1 ), VLA-5 (Integrin α 5 β 1 ), LFA-1 (Integrin α L β 2 ), and p11 (S100A10) are known to mediate ALL cell binding to osteoblasts and induce chemoprotective effects [8, 24-28]. Given our data supporting the requirement of direct contact between osteoblasts and ALL cells (Fig.…”

“…For example, we showed earlier that osteoblasts can protect ALL cells from cell death induced by treatment with chemotherapeutic drugs dexamethasone and vincristine [8]. In this study, cytarabine treatments (at IC50 concentrations) had significantly reduced efficiency in inducing cell death in REH, Nalm6 and CCRF-CEM cells cocultured with osteoblasts compared to treatments in monoculture (Fig.…”

“…Our lab has previously identified that disrupting the interaction between p11 protein (S100A10) and annexin II was able to chemosensitize ALL cells in co-culture with osteoblasts [8]. Natalizumab, which specifically targets integrin alpha4 and disrupts stromal adhesion of ALL cells, is currently being tested in clinical trials to block integrin alpha4 chemoprotective activity [9].…”

Multiple functions of S100A10, an important cancer promoter

“…S100A10 may also be linked to drug resistance. Inhibition of ANXA2‐S100A10 complex formation or the knockdown of S100A10 can increase the sensitivity of leukemia cells to vincristine . Increased S100A10 expression has been shown to be associated with tamoxifen resistance in breast cancer cells and breast cancer tissue .…”

“…An ANXA2 peptide which interferes with ANXA2‐S100A10 complex formation prevents binding of prostate cancer cells and multiple myeloma cells to osteoblasts . S100A10 antibodies are effective in reducing leukemia cell homing to the bone marrow in vivo . A number of small molecules that inhibit the formation of the complex have been identified .…”