title: 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(-) 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.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lilly
authors.forename: Farhat L
authors.initials: FL
authors.lastname: Khanim
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Hayden
authors.forename: Quang T
authors.initials: QT
authors.lastname: Luong
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bunce
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D018396:Mucin-1 / Q000096:biosynthesis; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D039481:CD11b Antigen; C509295:ITGAM protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C060192:MUC1 protein, human; D018396:Mucin-1; D054778:NM23 Nucleoside Diphosphate Kinases; D019009:Proto-Oncogene Proteins c-kit; C517938:NME1 protein, human