Abstract
The bone marrow microenvironment affects malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. Furthermore, the role of bone marrow stroma in regulating clinical responses to DNA methyltransferase (DNMTi) inhibitors is also poorly known. In this study, we performed a methylome analysis of DNA from bone marrow-derived stromal cells from patients with myelodysplastic syndrome (MDS) and observed generalized aberrant hypermethylation of cytosine occurring preferentially outside the CpG islands. The stroma of patients treated with 5-azacytidine showed no abnormal methylation, and DNMTi treatment of the primary stroma of MDS increased its ability to support erythroid differentiation. Integrative expression analysis revealed that the WNT pathway antagonist, FRZB, was abnormally hypermethylated and underexpressed in the MDS stroma. This result was confirmed in an independent pool of sorted MDS-derived primary mesenchymal cells. We document the activation signature of WNT/b-catenin on CD34ºcells from advanced cases of MDS, where it has been associated with a poor prognosis. Constitutive activation of b-catenin in hematopoietic cells resulted in lethal myeloid disease in the NUP98–HOXD13 MDS mouse model, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment that lead to b-catenin activation and MDS disease progression.
| original language | American English) |
|---|---|
| Pages (of-para) | 4846-4857 |
| Page number | 12 |
| Daily | cancer research |
| Tom | 77 |
| Issue number | 18 |
| Two | |
| Country | Published -September 15, 2017 |
Study Areas ASJC Scopus
- Oncology
- cancer research
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Bhagat , T.D. , Chen , S. , Bartenstein , M. , Barlowe , AT , Von Ahrens , D. , Choudhary , GS , Tivnan , P. , Amin , E. , Marcondes , AM , Sanders , MA , Hoogenboezem , R.M. [ PMC free article ] [ PubMed ] [ Cross Ref, Mantzaris, I., Sukrithan, V., Laurence, R., Lopez, R., Bhagat, P., Giricz, O., ... Verma, A.(2017).The epigenetically abnormal stroma in MDS propagates the disease by activating Wnt/β-catenin.cancer research,77(18), 4846-4857.https://doi.org/10.1158/0008-5472.CAN-17-0282
The epigenetically abnormal stroma in MDS propagates the disease by activating Wnt/β-catenin./Bhagat, Tushar D.; Chen, Si; Bartenstein, Mathias I.
C:cancer research, t. 77, nº 18, 15.09.2017, p. 4846-4857.
discoveries:Contribution to the magazine›Article›reviewing
Bhagat, TD, Chen, S, Bartenstein, M, Barlowe, AT, Von Ahrens, D, Choudhary, GS, Tivnan, P, Amin, E, Marcondes, AM, Sanders, MA, Hoogenboezem, RM, Kambhampati, S, Ramachandra , N, Mantzaris, en, Sukrithan, V, Laurence, R, Lopez, R, Bhagat, P, Giricz, O, Sohal, D, Wickrema, A, Yeung, C, Gritsman, K, Aplan, P, Hochedlinger, K, Yu, YPradhan, K., Zhang, J, Grely, JM, Mukherjee S, Pellagatti A, Boultwood J, It will be, Steidl, U, Raaijmakers, MHGP, Deeg, HJ, Kharas, MG2017, 'The epigenetically abnormal stroma in MDS propagates the disease by activating Wnt/β-catenin',cancer research, Tom. 77, no. 18, p. 4846-4857.https://doi.org/10.1158/0008-5472.CAN-17-0282
Bhagat TD, Chen S, Bartenstein M, Barlowe AT, Von Ahrens D, Choudhary GS i in.The epigenetically abnormal stroma in MDS propagates the disease by activating Wnt/β-catenin.cancer research. September 15, 2017;77(18):4846-4857. doi: 10.1158/0008-5472.CAN-17-0282
Bhagat, Tushar D.; Chen, Si; Bartenstein, Matthias i in. /The epigenetically abnormal stroma in MDS propagates the disease by activating Wnt/β-catenin. C:cancer research. 2017; t. 77, nº 18. s. 4846-4857.
@article{91186d65ad274af582c872ed11ae1642,
title = "Epigenetically abnormal stroma in MDS propagates disease by activating Wnt/β-catenin",
abstract = "The bone marrow microenvironment affects malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. Furthermore, the role of bone marrow stroma in regulating clinical responses to DNA methyltransferase (DNMTi) inhibitors is also poorly understood In this study, we performed methylome analysis of DNA from bone marrow-derived stromal cells from patients with myelodysplastic syndrome (MDS) and observed a common abnormal hypermethylation of cytosine occurring preferentially outside the CpG islands. did not show abnormal methylation and primary treatment DNMTi The MDS stroma increased its ability to support differentiation Integrative expression analysis showed that the WNT pathway antagonist, FRZB, was abnormally hypermethylated and underexpressed in the MDS stroma.This finding was confirmed in an independent set of sorted MDS-derived primary mesenchymal cells.We document a signature of WNT/b-catenin activation in CD34{\th} cells from advanced cases of MDS, where it was associated with a poor prognosis. Constitutive activation of b-catenin in hematopoietic cells resulted in lethal myeloid disease in the NUP98–HOXD13 MDS mouse model, confirming its role in disease progression. Our results identify novel epigenetic changes in the bone marrow microenvironment that lead to b-catenin activation and MDS disease progression.”,
autor = "Bhagat, {Tushar D.} i Si Chen oraz Matthias Bartenstein i Barlowe, {A. Trevor} i {Von Ahrens}, Dagny i Choudhary, {Gaurav S.} oraz Patrick Tivnan i Elianna Amin i Marcondes, {A. Mario} e Sanders, {Mathijs A.} e Hoogenboezem, {Remco M.} e Suman Kambhampati e Nandini Ramachandra e Iaonnis Mantzaris e Vineeth Sukrithan e Remi Laurence e Robert Lopez e Prafulla Bhagat e Orsi Giricz e Davendra Sohal e Amittha Wickrema e Cecilia Yeung e Kira Gritsman e Peter Aplan e Konrad Hochedlinger e Yiting Yu e Kith Pradhan e Jinghang Zhang e Greally, {John M.} e Siddhartha Mukherjee e Andrea Pellagatti e Jacqueline Boultwood e Britta Will e Ulrich Steidl e Raaijmakers, {Marc H.G.P.} i Deeg, {H. Joachim} i Kharas, {Michael G.} i Amit Verma”,
note="Funding information: This work was supported by the NIH (R01s HL116336, DK103961), the Leukemia and Lymphoma Society, and the Department of Defense (for A. Verma). MG Kharas was supported by the US NIH Career Development Award National Institute of Diabetes and Digestive and Kidney Diseases and NIDDKNIH R01-DK101989-01A1, Louis V Gerstner Young Investigator Award and American Society of Hematology Junior Scholar Award, Kimmel Scholar Award and V-Scholar Award. Society (KWF Kankerbes-trijding; EMCR 2010 -4733), the Netherlands Organization for Scientific Research (NWO90700422) and the Dutch Genomics Initiative (40-41009-98-11062). A. Pellagatti and J. Boultwood were supported by Bloodwise UK T.D. Bhagat received a NYSTEM scholarship. Publisher copyright: {\textcopyright}2017 AACR.",
again = "2017",
month = september,
day = "15",
doi = "10.1158/0008-5472.CAN-17-0282",
language = "English (US)",
volume = "77",
pages = "4846--4857",
journal = "Cancer Research",
issn = "0008-5472",
number = "18",
}
WEEK
T1 - Epigenetically abnormal stroma in MDS propagates disease by activating Wnt/β-catenin
AU – Bhagat, Tushar D.
AU - Chen, Si
AU—Bartenstein, Matthias
AU — Barlowe, A. Trevor
AU - Von Ahrens, Dagny
AU – Choudhary, Gaurav S.
AU - Tivnan, Patrick
PS - Amen, Elianna
AU - Marcondes, A. Mario
AU — Sanders, Mathijs A.
AU – Hoogenboezem, Remco M.
AU - Kambhampati, Suman
AU - Ramachandra, Nandini
AU - Mantzaris, Iaonnis
AU - Sukrithan, Vineeth
AU — Laurence, Remi
AU-Lopez, Robert
AU - Bhagat, Prafulla
AU – Giricz, Orsi
AU - Sohal, Davendra
AU - Wickrema, Amittha
AU - Yeung, Cecilia
AU - Gritsman, Kira
AU – Aplan, Piotr
AU – Hochedlinger, Konrad
AU - Yu, Yiting
AU - Pradhan, Keith
AU - Zhang, Jinghang
AU – Grely, John M.
AU - Mukherjee, Siddhartha
AU – Pellagatti, Andrea
AU - Boultwood, Jacqueline
AU - Will, Britta
AU—Steidl, Ulrich
AU - Raaijmakers, Marc H.G.P.
AU - Deeg, H. Joachim
AU – Kharas, Michael G.
AU - Verma, Amit
N1 - Funding Information: This work was supported by the NIH (R01s HL116336, DK103961), the Leukemia and Lymphoma Society, and the Department of Defense (for A. Verma). MG Kharas was supported by the US NIH National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award and NIDDKNIH R01-DK101989-01A1, Louis V Gerstner Young Investigator Award and American Society of Hematology Junior Scholar Award, Kimmel Scholar Award and V-Research Award. The MHGP Raaijmakers was funded by grants from the Dutch Cancer Society (KWF Kankerbes-trijding; EMCR 2010-4733), the Netherlands Research Organization (NWO90700422) and the Dutch Genomics Initiative (40-41009-98-11062). A. Pellagatti and J. Boultwood were supported by Bloodwise UK. TD Bhagat is a NYSTEM.Publisher Fellow Copyright: © 2017 AACR.
PY - 2017/09/15
A1 - 2017/09/15
N2 - The bone marrow microenvironment affects malignant hematopoiesis, but it has not been elucidated how it promotes leukemogenesis. Furthermore, the role of bone marrow stroma in regulating clinical responses to DNA methyltransferase (DNMTi) inhibitors is also poorly known. In this study, we performed a methylome analysis of DNA from bone marrow-derived stromal cells from patients with myelodysplastic syndrome (MDS) and observed generalized aberrant hypermethylation of cytosine occurring preferentially outside the CpG islands. The stroma of patients treated with 5-azacytidine showed no abnormal methylation, and DNMTi treatment of the primary stroma of MDS increased its ability to support erythroid differentiation. Integrative expression analysis revealed that the WNT pathway antagonist, FRZB, was abnormally hypermethylated and underexpressed in the MDS stroma. This result was confirmed in an independent pool of sorted MDS-derived primary mesenchymal cells. We document a signature of WNT/b-catenin activation in CD34+ cells from advanced cases of MDS, where it has been associated with a poor prognosis. Constitutive activation of b-catenin in hematopoietic cells resulted in lethal myeloid disease in the NUP98–HOXD13 MDS mouse model, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment that lead to b-catenin activation and MDS disease progression.
AB - The bone marrow microenvironment affects malignant hematopoiesis, but it has not been elucidated how it promotes leukemogenesis. Furthermore, the role of bone marrow stroma in regulating clinical responses to DNA methyltransferase (DNMTi) inhibitors is also poorly known. In this study, we performed a methylome analysis of DNA from bone marrow-derived stromal cells from patients with myelodysplastic syndrome (MDS) and observed generalized aberrant hypermethylation of cytosine occurring preferentially outside the CpG islands. The stroma of patients treated with 5-azacytidine showed no abnormal methylation, and DNMTi treatment of the primary stroma of MDS increased its ability to support erythroid differentiation. Integrative expression analysis revealed that the WNT pathway antagonist, FRZB, was abnormally hypermethylated and underexpressed in the MDS stroma. This result was confirmed in an independent pool of sorted MDS-derived primary mesenchymal cells. We document a signature of WNT/b-catenin activation in CD34+ cells from advanced cases of MDS, where it has been associated with an unfavorable prognosis. Constitutive activation of b-catenin in hematopoietic cells resulted in lethal myeloid disease in the NUP98–HOXD13 MDS mouse model, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment that lead to b-catenin activation and MDS disease progression.
UR — http://www.scopus.com/inward/record.url?scp=85031430256&partnerID=8YFLogxK
URL — http://www.scopus.com/inward/citedby.url?scp=85031430256&partnerID=8YFLogxK
U2-10.1158/0008-5472.CAN-17-0282
DO-10.1158/0008-5472.CAN-17-0282
M3 - Article
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SN-0008-5472
VL - 77
SP-4846
PE - 4857
JO - Cancer Research
JF - Cancer Research
It's - 18
AND -
FAQs
What is the role played by Wnt beta catenin signaling pathway in acute lymphoblastic leukemia? ›
The Wnt/β-catenin pathway regulates several physiological processes such as embryogenic development, adult tissue homeostasis, wound healing, and stem cell maintenance by regulating the cell fate, differentiation, apoptosis, polarity, and migration [8].
Does MDS cause inflammation? ›Contribution of hematopoietic cells from the MDS clone to inflammation. Mature cells that derive from the MDS progenitor cell(s) can produce pro-inflammatory chemokines and cytokines which could contribute to a microenvironment which favors aberrant vs normal hematopoiesis.
What does the Wnt beta-catenin pathway do? ›The Wnt/β-catenin signaling pathway is an evolutionarily conserved mechanism that plays a preeminent role in maintaining cellular homeostasis. It regulates embryo development, cell proliferation and differentiation, apoptosis, and inflammation-associated cancer (1).
What are the effects of Wnt β catenin signaling pathway? ›Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal.
What can trigger MDS? ›Most myelodysplastic syndromes have no known cause. Others are caused by exposure to cancer treatments, such as chemotherapy and radiation, or to toxic chemicals, such as benzene.
Does MDS always turn into leukemia? ›An MDS will develop into acute myeloid leukemia (AML) about 30% of the time. In the past, an MDS was classified as a disease that was not likely to develop into cancer and it was called pre-leukemia. Now that more is known about MDSs, they are considered to be a form of cancer.
What are signs that MDS is progressing? ›- weakness, tiredness and occasional breathlessness (because of the low number of red blood cells)
- frequent infections (because of the low number of white blood cells)
- bruising and easy bleeding, such as nosebleeds (because of the low number of platelets)
The Wnt/β-catenin pathway is activated when a Wnt ligand binds to a seven-pass transmembrane Frizzled (Fz) receptor and its co-receptor, low-density lipoprotein receptor related protein 6 (LRP6) or its close relative LRP5.
What disease is Wnt β catenin signaling? ›The Importance of WNT Signaling
The WNT pathway is most famously known for its involvement in hereditary familial adenomatous polyposis (FAP), where a mutated APC tumor suppressor gene fails to regulate β-catenin regulation, allowing tumor cells to progress towards malignancy [39,40].
The Wnt/β-catenin signaling pathway is complex and consists of numerous receptors, inhibitors, activators, modulators, phosphatases, kinases and other components. However, there is one central, critical molecule to this pathway, β-catenin.
What happens when there is too much beta catenin? ›
Excessive β-Catenin in Excitatory Neurons Results in Reduced Social and Increased Repetitive Behaviors and Altered Expression of Multiple Genes Linked to Human Autism.
What happens when Wnt is inhibited? ›Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors.
What is the effect of beta catenin? ›β-Catenin signaling is another pro-proliferative and prosurvival signal that plays a vital role during liver regeneration after PH. β-Catenin has been known to have a positive role in liver growth. Mice overexpressing β-catenin in the liver have increased hepatocyte proliferation and a 15% increase in liver size.
What is the most common mutation in MDS? ›Splicing Factor Mutations. RNA splicing factor mutations represent the most prevalent somatic gene mutations in MDS, of which the most commonly affected are those in the U2RNP complex, including SF3B1, SRSF2, U2AF1, and ZRSR2, and less commonly, SF1, U2AF2, and SF3A1.
What is the best treatment for MDS? ›Treatments include chemotherapy or a donor stem cell transplant. The only way to cure MDS is to have intensive treatment with a stem cell transplant from a donor.
How do you reverse MDS? ›Treatments. The only known cure for MDS is allogeneic blood and marrow transplantation (BMT).
Can MDS come back after bone marrow transplant? ›BMT, also known as a bone marrow transplant or blood stem cell transplant, can treat patients who have MDS, including older patients. It replaces the unhealthy blood-forming cells (stem cells) with healthy ones. For some people, transplant can cure MDS. For others, it may delay relapse (the MDS coming back).
How often does MDS turn into AML? ›Over time, about one-third of all MDS cases evolve to become AML. The risk of developing AML depends largely on which MDS subtype you have at the time of diagnosis. A patient with lower-risk MDS has up to a 2 in 10 chance of developing AML.
Can MDS go into remission without treatment? ›Spontaneous remission (SR) of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in the absence of disease-modifying therapy is rare.
What is the most important prognosis indicator in MDS? ›Karyotype has become one of the most important prognostic factors in MDS.
What is the most common cause of death in MDS? ›
Death from MDS is often caused by bleeding and/or infection from low blood cell counts or after the disease becomes acute myeloid leukemia (AML). About a third of patients with MDS develop AML. Talk with your doctor if you have any questions about this information.
What should I avoid if I have MDS? ›- fully cook all meat, fish, and egg dishes.
- avoid fruits and vegetables that you cannot peel.
- avoid raw foods.
- avoid unpasteurized cheese, milk, and other dairy products.
- avoid unpasteurized juices.
This pathway is not only important in mineralized tissue growth and development, but for modulation of the skeleton in response to loading and unloading and the viability and health of the adult and aging skeleton.
What signaling pathway is beta-catenin involved in? ›The Wnt/β-catenin signaling pathway, also called the canonical Wnt signaling pathway, is a conserved signaling axis participating in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, invasion and tissue homeostasis [1,2,3].
What is the role of the Wnt gene family? ›The Wnt gene family is known to regulate the cell fate and cell-cell interactions of multipotential cells in a variety of tissues.
What is the role of the WNT Signalling pathway in the development of endothelial disorders in response to hyperglycaemia? ›Hyperglycaemia affects endothelial functions and induces inflammatory processes leading to atherosclerosis and impaired angiogenesis. Wnt signalling is activated during hyperglycaemia and causes endothelial dysfunction and EndoMT.
What is the role of the Wnt pathway in the formation development and degeneration of intervertebral discs? ›The Wnt pathway plays an important role in the growth, development, and degeneration of intervertebral discs (IVDs). In the embryonic stage, the Wnt pathway participates in the growth and development of IVD by promoting the transformation of progenitor cells into notochord cells and the extension of the notochord.
How is beta catenin activated? ›Recent analysis of Wnt pathway components in blood vessels revealed that the canonical Wnt–β-catenin pathway is present in vascular cells activated by a vascular lesion or an ischemia event, and this pathway appears to regulate vascular smooth muscle proliferation and apoptosis.
What genes are involved in the Wnt signaling pathway? ›Components of this pathway include the adenomatous polyposis coli (APC) gene which is mutated in roughly 80% of CRC, AXIN 1 and 2, and glycogen synthase kinase 3β (GSK-3β) [3]. Downstream genes in this pathway include c-myc, c-jun, and Cyclin D1 (CCND1).
What genes are activated by beta catenin? ›β-catenin translocates to the nucleus and interferes with the TCF- LEF co-transcription factors. This leads to the stimulation of several β-catenin target genes (CYCLIN D1, c-MYC, PDK, MTC-1, MMP7, fibronectin, COX-2, AXIN-2) (7, 8, 21, 22) (Figure 2).
What cancers are beta catenin driven? ›
In more than half of all cancer cases, such as colorectal carcinoma, breast cancer, liver carcinoma, melanoma and leukemia, β-catenin accumulates within the nucleus or cytoplasm [6–10].
What is the Wnt beta catenin pathway mutation? ›Mutation-induced activation of WNT-β-catenin signalling is a frequent driver event in human cancer. Sustained WNT-β-catenin pathway activation endows cancer cells with sustained self-renewing growth properties and is associated with therapy resistance.
What is the target of beta catenin? ›β-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B.
Where does Wnt Signalling occur? ›Wnt signaling plays a critical role in embryonic development. It operates in both vertebrates and invertebrates, including humans, frogs, zebrafish, C. elegans, Drosophila and others. It was first found in the segment polarity of Drosophila, where it helps to establish anterior and posterior polarities.