Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans

Dieguez-Acuña, Francisco J.; Gygi, Stephen; Davis, Miriam; Faustman, Denise L.

doi:10.1038/sj.leu.2404927

Cited by 15 publications

(17 citation statements)

References 7 publications

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“…The expression of Hox11 in splenic stem cells suggests that the spleen harbors into adulthood a previously unknown reservoir of stem cells that may descend back to embryonic life. Strikingly, the same reservoir of Hox11 stem cells is found in the spleen of normal human adults (Dieguez-Acuna et al, 2007). Post-mortem analysis of human organs being harvested for donation revealed that Hox11 stem cells were only located in the spleen, as opposed to other organs, and were found in the same general capsular location seen in mice.…”

Section: Cell Origin and Plasticity: Splenic Stem Cells Express Homentioning

confidence: 89%

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

Faustman

Davis

2010

The International Journal of Biochemistry & Cell Biology

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The view of the spleen as an unnecessary organ has been shattered. The evidence shows the spleen to be a source of naturally-occurring multipotent stem cells with possibly pluripotent potential. The stem cells are sequestered in the spleen of not only of animals but also of normal human adults. The reservoir of cells is set for differentiation and they need not be manipulated in vitro or ex vivo before autologous or heterologous use. Splenic stem cells, of Hox11 lineage, have been found in disease or injury to differentiate into pancreatic islets, salivary epithelial cells and osteoblast-like cells, cranial neurons, cochlea, lymphocytes, and more differentiated immune cells that repair injured heart cells. Injury or disease in target tissues induces these stem cells, still in the spleen, to upregulate the same embryonic transcription factors artificially introduced into induced pluripotent stem cells (iPS). Splenic stem cells may have broad pluripotent potential, but unlike iPS cells, possess low oncogenic risk.

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Section: Cell Origin and Plasticity: Splenic Stem Cells Express Homentioning

confidence: 89%

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

Faustman

Davis

2010

The International Journal of Biochemistry & Cell Biology

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“…We concluded that CFA was insufficient to decrease the inflammatory cell infiltrates in SGs and started to investigate for additional approaches to our proposed combined therapy. Recent evidence from our collaborators (DL Faustman and S Kodama) indicated that multipotent stem cells of non-lymphoid lineage (CD45-negative; CD45 − ) from the spleen contributed to the regeneration of bone, inner ear, cranial nerves, islets, hearts, and of particular interest to our work, salivary glands [12], [13], [14], [15]. The spleen and bone marrow are closely related organs, and both are among the first sites of hematopoiesis during gestation.…”

Section: Introductionmentioning

confidence: 85%

Mesenchymal Stromal Cells Improve Salivary Function and Reduce Lymphocytic Infiltrates in Mice with Sjögren's-Like Disease

Khalili

Liu

Kornete³

et al. 2012

PLoS ONE

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BackgroundNon-obese diabetic (NOD) mice develop Sjögren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45−/TER119− cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined.Methodology/Principal FindingsDonor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45−/TER119− cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3+ (Treg) cell was increased. MSC-therapy alone reduced inflammation (TNF-α, TGF-β), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF).Conclusions/SignificanceThe combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands.

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“…In a previous paper (Dieguez-Acuna et al, 2007), spleens were removed from CByB6F 1 mice and divided into CD45 + and CD45 - populations by CD45 magnetic bead separations. Whole cell protein fractions were prepared and resolved by 1D SDS PAGE and 14 trypsin digests were prepared and analyzed by LC-MS/MS in 4 to 6 replicates.…”

Section: Figures and Tablesmentioning

confidence: 99%

“…These stem cells are non-lymphoid (CD45-) cells, contrary to the spleen's predominant cell type, CD45+ lymphoid cells. The CD45- stem cells not only regenerate the structure or function of several other tissues and portions of organs, but they do so without in vivo or ex vivo manipulation (Dieguez-Acuna et al, 2007, Kodama et al, 2003, Kodama et al, 2005a, Lonyai et al, 2008). Our next step was to characterize in mice the proteomes of the non-lymphoid and lymphoid populations with new instrumentation, namely state-of-the-art mass spectrometry (LTQ-FT) followed by shotgun and subtractive proteomics.…”

Section: Introductionmentioning

confidence: 99%

“…That hypothesis holds that cancers arise from, and are sustained by, rare stem cells that become transformed into malignant cells (Dalerba et al, 2007). It has been proposed that CD45-splenic stem cells expressing HOX11+ are precursors of two rare spontaneous cancers that express HOX11, lymphoblastic leukemias of T cell lineage (T-ALL) and select pediatric brain tumors (Dieguez-Acuna et al, 2007). However, the rarity of these cancers implies that Hox11+ CD45-splenic stem cells are infrequently transformed to malignancies, most likely resulting from naturally occurring alterations in regulatory controls.…”

Section: Introductionmentioning

confidence: 99%

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Proteomics identifies multipotent and low oncogenic risk stem cells of the spleen

Dieguez-Acuña

Kodama

Okubo

et al. 2010

The International Journal of Biochemistry & Cell Biology

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The adult spleen harbors a population of naturally occurring multipotent stem cells of non-lymphoid lineage (CD45-). In animal models, these splenic stem cells can directly or indirectly contribute to regeneration of bone, inner ear, cranial nerves, islets, hearts and salivary glands. Here we characterize the CD45-stem cell proteome to determine its potential broader multipotency versus its protection from malignant transformation. Using state-of-the-art proteomics and in vivo testing, we performed functional analyses of unique proteins of CD45-(non-lymphoid) splenic stem cells, as compared with CD45+ (lymphoid) cells. CD45-stem cell-specific proteins were identical to those in iPS, including OCT3/4, SOX2, KLF4, c-MYC and NANOG. They also expressed Hox11, Gli3, Wnt2, and Adam12, the benchmark transcription factors of embryonic stem cells. These transcription factors were functional because their mRNA was upregulated in the spleen in association with ongoing damage to the pancreas and salivary glands, organs to which they normally contribute stem cells. We also show low likelihood of malignant transformation. Our proteomic and functional analyses reveals that naturally occurring CD45-stem cells of the spleen are the first-ever candidates for naturally occurring population of embryonic and iPS cells with low oncogenic risk. Given their presence in normal humans and mice, splenic stem cells are poised for translational research.

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Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans

Cited by 15 publications

References 7 publications

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

Mesenchymal Stromal Cells Improve Salivary Function and Reduce Lymphocytic Infiltrates in Mice with Sjögren's-Like Disease

Proteomics identifies multipotent and low oncogenic risk stem cells of the spleen

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