Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we asses...

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Published in:Blood cancer journal (New York) 2012-09, Vol.2 (9), p.e87-e87
Main Authors: Kobune, M, Iyama, S, Kikuchi, S, Horiguchi, H, Sato, T, Murase, K, Kawano, Y, Takada, K, Ono, K, Kamihara, Y, Hayashi, T, Miyanishi, K, Sato, Y, Takimoto, R, Kato, J
Format: Article
Language:English
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631/136/2091
631/208/199
692/699/67/1990/1673
692/699/67/1990/283/1897
Biomedical and Life Sciences
Biomedicine
Cancer Research
Hematology
Oncology
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Summary:Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34 + cells, CD34 + blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34 + acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO + leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO + leukemic cell proliferation. The demethylating agent, 5-aza-2′-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.
ISSN:2044-5385
2044-5385
DOI:10.1038/bcj.2012.36