BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

BAG3 is expressed at low levels in normal blood cells, whereas it is highly expressed both in primary leukemic blasts or established cells lines from leukemic patients. 21, 22 Furthermore, its levels are markedly higher in drug-resistant patients compared with patients that resulted responsive to chemotherapy. One mechanism responsible for bag3 overexpression in leukemic cells relies on the effect of the WT1 transcription factor on the bag3 gene promoter. 49 WT1 is overexpressed in acute lymphoblastic and myeloblastic leukemia, and high levels of the protein are associated with a poor response to therapy. 50 We recently showed that the WT1 isoform þ KTS was able to positively regulates BAG3 expression by a transcriptional mechanism, via a direct binding on two WT1 consensus sites on the bag3 gene promoter. WT1 knockdown induces apoptosis, whereas its overexpression protects leukemic cells from apoptosis inducers; these effect are in part because of the modulation of BAG3 protein levels. 49 The role of BAG3 modulation is even more evident in primary human leukemia cells. Indeed in leukemic cells from 24 patients affected by B-cell chronic lymphocytic leukemia (B-CLL) 21 and from 11 children affected by acute lymphoblastic leukemia, 22 we observed that BAG3 down-modulation by specific antisense oligodeoxynucleotides results in enhancing the percentage of apoptotic elements by 4100%. Cell apoptosis was enhanced in cells either untreated or incubated with chemotherapeutic drugs. Those were the first reported evidence of the apoptosisregulating activity of BAG3 protein in primary tumors. 21, 22 We also showed that BAG3 down-modulation increased apoptosis of primary normal human peripheral blood mononuclear cells as well as of leukemic cells incubated with agents able to induced oxidative stress. 39 Furthermore, a physical interaction was observed between BAG3 and the Btk under oxidative stress conditions. All those evidences assign to BAG3 a critical role in the leukemic cell survival and responsiveness to chemotherapy and should prompt investigators to further investigate its role in these deseases and the possibility of exploiting it as a molecular target.