Nonhematopoietic cells represent a more rational target of in vivo hedgehog signaling affecting normal or acute myeloid leukemia progenitors
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abstract
Recent work has shown that leukemic stem cell self-renewal in chronic myeloid leukemia is dependent on cell-intrinsic hedgehog (Hh) signaling, and early clinical trials suggest that targeting this pathway is also therapeutic in patients with acute myeloid leukemia (AML). In this study, we aimed to better understand Hh signaling in normal hematopoiesis and AML by molecularly and functionally analyzing more than 200 primary human AML patient samples compared with nonleukemic controls. Gene expression analysis indicated that Hh pathway transcripts were similarly regulated in AML and nonleukemic controls, regardless of whether samples were purified based on primitive phenotypes. Consistent with these results, pharmacologic inhibition of Smoothened (SMO) did not preferentially reduce in vitro colony formation of AML versus normal progenitors. Using a unique analytic approach, messenger RNA expression of membrane receptor SMO was found to be unexpectedly rare within all hematopoietic samples analyzed, which is indicative of heterogeneity at the level of Hh signaling machinery. In contrast, abundant SMO expression could be readily detected in the nonhematopoietic fraction of human and murine bone marrow (BM) cells. Our predictions of increased SMO(+) cell frequencies within nonhematopoietic BM fractions were further supported by single-cell protein analyses. Although we did not find support for cell-autonomous sensitivity of AML cells to Hh pathway inhibition, we alternatively suggest that nonhematopoietic BM cells represent an indirect target through which primitive normal and leukemic cells can be modulated. These findings suggest current approaches to applying Hh inhibition should be carefully reevaluated to account for BM niche cell regulation that might be selectively Hh responsive.
