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(-) and CD11b(+) 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 1β (IL1β) 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 IL1β 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.
Highlights
A murine Nm23 gene identified by Steeg and colleagues [1] was the first metastasis suppressor gene discovered
To further examine the role of extracellular Nm23-H1 in acute myeloid leukemia (AML), primary AML cells from 18 patients were cultured in serum-free conditions with and without 2 mg/mL rNm23-H1 and cell survival analyzed at day 5. rNm23-H1 enhanced overall AML cell survival compared with elution buffer control (P < 0.001; Fig. 1A)
We show a strong association between the ability of the AML cells to bind rNm23-H1 at the cell surface and cell survival in vitro
Summary
A murine Nm23 gene identified by Steeg and colleagues [1] was the first metastasis suppressor gene discovered. The authors showed that high levels of Nm23 mRNA correlated with low metastatic potential, whereas highly metastatic cells expressed Nm23 mRNA at a lower level [1]. 10 human Nm23 genes have been identified, which all share functionally diverse isoforms of a nucleoside diphosphate kinase domain [2]. The Nm23-H1 and -H2 genes have been extensively studied in human breast carcinomas, melanomas, and ovarian cancers, where the general trend is an inverse. Relationship between Nm23 expression and metastatic stage [3]. This has been supported by transfection experiments in breast cancer MDA cell lines, where overexpression of Nm23H1 and -H2 genes resulted in decreased metastatic potential [4,5,6]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call