Stromal Cells Expressing Hedgehog-interacting Protein Regulate the Proliferation of Myeloid Neoplasms

Overview

Journal Blood Cancer J

Date 2012 Sep 11

PMID 22961059

Citations 28

Authors

M Kobune

S Iyama

S Kikuchi

H Horiguchi

T Sato

K Murase

Y Kawano

K Takada

K Ono

Y Kamihara

T Hayashi

K Miyanishi

Y Sato

R Takimoto

J Kato

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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