Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation

Bhardwaj, Gunjan; Murdoch, Barbara; Wu, Dongmei; Baker, Darren P.; Williams, Kevin P.; Chadwick, Kristin; Ling, Leona; Karanu, Francis; Bhatia, Mickie

doi:10.1038/84282

Cited by 589 publications

(422 citation statements)

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“…pathway is involved in the maintenance of adult stem cells and production of the progeny that differentiates into specialized cell lineages. 3,[18][19][20] SHH also has been shown to regulate the proliferation and differentiation of hematopoietic precursor cells. In the thymus, SHH is a regulator of T-cell differentiation and T-cell receptor repertoire selection.…”

Section: Discussionmentioning

confidence: 99%

“…2 Recent studies also implicate these proteins in cell fate determination and self-renewal of the hematopoietic system, and sonic hedgehog (SHH) is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. 3,4 SHH ligand interacts with a receptor complex composed of two proteins, patched (PTCH) and smoothened (SMO). PTCH is the SHH ligand-binding subunit and SMO is the signal transduction component.…”

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confidence: 99%

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Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

et al. 2009

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Dysregulation of the sonic hedgehog (SHH) signaling pathway has been shown in several cancer types, but has not been explored in diffuse large B-cell lymphoma. We assessed 67 cases of diffuse large B-cell lymphoma for expression of SHH (ligand), GLI1, GLI2 and GLI3 (transcriptional effectors of SHH signaling), and the ATPbinding cassette (ABC)G2 (a downstream target of SHH signaling), using immunohistochemistry. For comparison, we assessed the expression levels of these proteins in 28 cases of follicular lymphoma, 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, and 5 reactive lymph nodes. In diffuse large B-cell lymphoma, SHH was expressed in 61 of 67 (91%) cases, GLI1 in 62 of 67 (93%), GLI2 in 41 of 56 (73%), and GLI3 in 22 of 56 (39%). Expression of ABCG2 was detected in 52 of 55 (95%) cases and was high in 15 (27%) cases. SHH expression positively correlated with expression levels of ABCG2 (P ¼ 0.05). Patients with diffuse large Bcell lymphoma with high ABCG2 expression showed significantly shorter overall survival (P ¼ 0.031) and failurefree survival (P ¼ 0.029) compared with patients with tumors with low or no expression of ABCG2. Diffuse large B-cell lymphomas expressed SHH, and GLI1, GLI2, and GLI3 more frequently and more intensely than cases of follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. In conclusion, our data show that SHH signaling proteins and ABCG2 are aberrantly expressed in diffuse large B-cell lymphoma and that ABCG2 expression has prognostic implications. These findings also provide evidence that dysregulation of the SHH pathway may be involved in the pathogenesis of diffuse large B-cell lymphoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

et al. 2009

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“…Rather, Bmi1 controls cellular proliferation by silencing the CDKN2A locus that encodes the cell-cycle inhibitor genes p16 Ink4a and p19 ARF (Jacobs et al, 1999). Other pathways implicated in HSC self-renewal control include the Wnt (b-catenin) (Reya et al, 2003), Notch (Varnum-Finney et al, 2000) and Shh (Bhardwaj et al, 2001) signaling pathways. Dissection of these pathways and elucidation of their interplay will be of great interest.…”

Section: Hox and The Leukemic Stem Cellmentioning

confidence: 99%

Hox genes in hematopoiesis and leukemogenesis

2007

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“…Other signaling pathways involved in stem cell selfrenewal include Notch, Sonic hedgehog (Shh), phosphatidylinositol-3 kinase (PIK3), and Homeobox (HOX) and Polycomb families, all of which are deregulated in hematopoietic and epithelial tumors 64,[66][67][68][69][70][71][72] . A crucial task for investigators is to search for genetic and functional similarities and differences between normal and cancer stem cell self-renewal pathways.…”

Section: Disruption Of Critical Self-renewal Pathwaysmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation

Cited by 589 publications

References 55 publications

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

Hox genes in hematopoiesis and leukemogenesis

Somatic stem cells and the origin of cancer

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