Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone

Abstract

Nm23-H1 plays complex roles in the development of diverse cancers including breast carcinoma, high-grade lymphomas, and acute myeloid leukemia (AML). In the case of AML and lymphomas, serum Nm23-H1 protein is elevated with the highest levels correlating with poorest prognosis. A recent study identified that this association is most likely causal in AML and that Nm23-H1 acts as an AML cell survival factor. In this study, we report heterogeneity in the ability of AML samples to bind and respond to Nm23-H1, and we offer evidence that binding is essential for improved survival. Further, we show that the subset of AMLs that bind Nm23-H1 do not do so through the putative Nm23-H1 receptor MUC1*. Although rNm23-H1 promoted the survival of the most primitive blasts within responding AMLs, it was not these cells that actually bound the protein. Instead, rNm23-H1 bound to more mature CD34 lo /CD34 À and CD11b þ cells, revealing an indirect survival benefit of Nm23-H1 on primitive blasts. In support of this finding, the survival of purified blast cells was enhanced by medium conditioned by more mature cells from the clone that had been stimulated by rNm23-H1. Levels of interleukin 1b (IL1b) and IL6 in rNm23-H1 conditioned medium mirrored the potency of the conditioned media to promote blast cell survival. Furthermore, Nm23-H1 expression was significantly associated with IL1b and IL6 expression in primary uncultured AML samples. These findings have implications for the role of Nm23-H1 in AML and its use as a prognostic marker. Additionally, they offer the first evidence of novel cross-talk between cell populations within the tumor clone. Cancer Res; 71(3); 1177-86. Ó2010 AACR.

Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

“…Moreover, NM23-H1 functions are not always intracellular, judging from activities mediated by extracellular NM23 (34,35). In particular, the protein is overexpressed in some tumors, including hematologic malignancies, and is present at elevated levels in patient sera, where the protein seems to promote tumor cell growth and survival by autocrine and/or paracrine mechanisms (36)(37)(38)(39). In the present study, we show that NM23-H1 lacking an MTD sequence does not efficiently enter cells.…”

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

“…The gene is highly conserved from yeast to humans, implying a critical developmental function. Cell surface nm23-H1 has been previously observed in non-Hodgkin lymphoma (NHL) cells (12,13) and certain myeloid cell lines (14,15). Specific studies (13,14) have demonstrated that tumors with a reduced expression of the nm23 gene are more prone to metastasis.…”

“…Cell surface nm23-H1 has been previously observed in non-Hodgkin lymphoma (NHL) cells (12,13) and certain myeloid cell lines (14,15). Specific studies (13,14) have demonstrated that tumors with a reduced expression of the nm23 gene are more prone to metastasis. It has been also previously documented that the expression of nm23-H1 transcripts and, more so, the levels of nm23-H1 protein in serum, provide strong indicators of prognosis, with higher values being associated with poorer overall survival (13–15).…”

NME1 (NME/NM23 nucleoside diphosphate kinase 1)

“…However, Bircan et al (Bircan et al, 2008) reported that the increased NME1 expression was of no prognostic value in a series of Hodgkin and non Hodgkin lymphoma. Pointing to a role of extracellular NME1, recombinant NME1 protein was shown to promote the survival of acute myeloid leukemia blast cells (Okabe-Kado et al, 2009a;Lilly et al, 2011) but to decrease the survival of primary cultured normal peripheral blood mononuclear cells (Okabe-Kado et al, 2009b).…”