Identification of NM23-H2 as a tumour-associated antigen in chronic myeloid leukaemia

Abstract

Therapeutic effects of haematopoietic stem cell transplantation are not limited to maximal chemoradiotherapy and subsequent bone marrow regeneration, but include specific as well as unspecific immune reactions known as graft-versus-leukaemia (GvL) effects. Specific immune reactions are likely to be particularly relevant to the long-term treatment of diseases, such as chronic myeloid leukaemia (CML), in which residual cells may remain quiescent and unresponsive to cytotoxic and molecular therapies for long periods of time. Specific GvL effects result from the expression on leukaemic cells of specific tumour-associated antigens (TAAs) in the context of HLA proteins. As human leukocyte antigen (HLA) types vary widely, the development of broadly applicable tumour vaccines will require the identification of multiple TAAs active in different HLA backgrounds. Here, we describe the identification of NM23-H2 as a novel HLA-A32-restricted TAA of CML cells and demonstrate the presence of specifically reactive T cells in a patient 5 years after transplantation. As the NM23 proteins are aberrantly expressed in a range of different tumours, our findings suggest potential applications beyond CML and provide a new avenue of investigation into the molecular mechanisms underlying CML.

A proteomic approach to identification of plutonium-binding proteins in mammalian cells

“…42, 43 NDK B has even been proposed as a biomarker for lung cancer; 44 and as a cell surface marker for leukemia cells. 45, 46 The uncharacterized 41.79 kDa predicted actin, gamma 1 propeptide-like protein from rat is a cytoplasmic protein found in non-muscle cells. It has not been well studied for metal binding but actin is well known to bind Ca 2+ and Mg 2+ ions with micromolar affinity.…”

Inhibition of nm23-H1 gene expression in chronic myelogenous leukemia cells

“…Given the widespread involvement of nm23 proteins in tumorigenesis, it will also be noteworthy to investigate the potential relevance of nm23-H2 as a therapeutic target in other cancers. The regulatory interdependence of nm23-H2 and c-myc provides a basis from which to design specific studies to elucidate the function of nm23 proteins in normal and leukemic cells, which may contribute to our understanding of the molecular mechanisms underlying the development and progression of CML (21). Future studies should investigate the association between nm23-H1 binding and responses to CML therapies, and aim to determine the nature of the nm23-H1 receptor in CML, which may provide a novel target for adjunctive therapies.…”

Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives

“…The protein expression level of Nm23-H2 is increased in mononuclear cells of peripheral blood from pre-transplant Philadelphia chromosome-positive CML patients compared with the control HLA-identical donor, with an interesting co-localization of Nm23-H2 and β-actin in the cytoplasm (Tschiedel et al 2008). Furthermore, Nm23-H2 overexpression correlates closely with the activity of the oncogenic Bcr-Abl fusion protein, a tyrosine kinase which acts as a GTPase-activating protein for Rac1 and Cdc42, independent of HLA type (Tschiedel et al 2012).…”