Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis

Toofan, Parto; Wheadon, Helen

doi:10.1042/bst20160104

Cited by 15 publications

(20 citation statements)

References 64 publications

(86 reference statements)

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“…BMP4, BMPR1A, and Id1 are commonly associated with cell survival probably by controlling cell proliferation and differentiation, as reported in normal and leukemic contexts 4 , 12 , 20 . In order to identify new BMP4/BMPR1A downstream partners, we evaluated the expression of other genes involved in cell survival, such as the p53 family members 27 .…”

Section: Resultsmentioning

confidence: 62%

“…More globally, understanding interactions between tumor stem cells (SCs) and their microenvironment is a challenge to develop strategies to avoid relapses after therapy. Among the main elements implicated in the crosstalk between the microenvironment and both normal and tumor SCs, we have investigated the role of bone morphogenetic proteins (BMPs), because they govern SC regulation including hematopoietic 4 , 5 , neural and epithelial systems 6 by directly and indirectly affecting their niche 7 – 9 . Alterations of the BMP signaling pathway have been observed in numerous cancers, in some cases closely associated with cancer stem cells (CSC) properties 10 .…”

Section: Introductionmentioning

confidence: 99%

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A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Voeltzel¹,

Flores-Violante²,

Zylbersztejn³

et al. 2018

Cell Death Dis

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In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

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Section: Resultsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Voeltzel¹,

Flores-Violante²,

Zylbersztejn³

et al. 2018

Cell Death Dis

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“…For example, the cross-talk between BMP and WNT pathways, which both converge to regulate the HOX gene expression through b-catenin, is involved in increasing CML-LSC self-renewal capacities. 50 In addition, in a normal context, we showed cross-talk between BMP4 and MEK or JAK/STAT 25 signaling, important pathways in CML TKI treatment survival. 41,51 Lastly, deregulation of the BMP pathway that persists under TKI could contribute to the enrichment of the TGFb signature in both BCR-ABL 1 SCs and [IM] M Proliferation ratio to untreated cells from newly diagnosed CP patients treated or not in serum-free media with IM at 1 or 2 mM, and with or without sBMPR1b.…”

Section: Discussionmentioning

confidence: 82%

Immature CML cells implement a BMP autocrine loop to escape TKI treatment

Grockowiak

Laperrousaz

Jeanpierre

et al. 2017

Blood

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The BCR-ABL specific tyrosine kinase inhibitors (TKI) changed the outcome of chronic myeloid leukemia (CML), turning a life-threatening disease into a chronic illness. However, TKI are not yet curative, because most patients retain leukemic stem cells (LSC) and their progenitors in bone marrow and relapse following treatment cessation. At diagnosis, deregulation of the bone morphogenetic protein (BMP) pathway is involved in LSC and progenitor expansion. Here, we report that BMP pathway alterations persist in TKI-resistant patients. In comparison with patients in complete cytogenetic remission, TKI-resistant LSC and progenitors display high levels of BMPR1b expression and alterations of its cellular localization. In vitro treatment of immature chronic phase CML cells with TKI alone, or in combination with interferon-α, results in the preferential survival of BMPR1b cells. We demonstrated persistent and increasing BMP4 production by patients' mesenchymal cells with resistance. Patient follow-up revealed an increase of BMPR1b expression and in BMP4 expression in LSC from TKI-resistant patients in comparison with diagnosis, while remaining unchanged in sensitive patients. Both leukemic and nonleukemic cells exhibit higher BMP4 levels in the bone marrow of TKI-resistant patients. Exposure to BMP2/BMP4 does not alter BCR-ABL transcript expression but is accompanied by the overexpression of TWIST-1, a transcription factor highly expressed in resistant LSC. By modulating BMP4 or BMPR1b expression, we show that these elements are involved in TKI resistance. In summary, we reveal that persistence of BMP alterations and existence of an autocrine loop promote CML-primitive cells' TKI resistance.

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“…They are the only known morphogenetic factors capable of inducing the differentiation of MSCs (21–24), and have been shown to play important roles in proliferation, hematopoiesis and the development of leukemia (25–27). There is increasing evidence linking BMPs to the transformation of the BMM (26,28,29) and this suggests a potential role of BMPs in leukemia. Along these lines, alterations in the BMP pathway resulting in MSC differentiation and the secretion of growth factors by MSCs has been shown to confer a growth advantage, as well as BMM transformation in AML (8).…”

Section: Introductionmentioning

confidence: 99%

AML‑derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562‑ADM fusiform transformation and chemoresistance

Cheng

et al. 2019

Oncol Rep

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Bone marrow-derived mesenchymal stem cells (MSCs), are the basic cellular components that make up the bone marrow microenvironment (BMM). In acute myeloid leukemia (AML), the morphology and function of MSCs changes in accordance with the transformation of the BMM. Moreover, the transformation of MSCs into osteoblasts is determined through the bone morphogenetic protein (BMP) pathway, ultimately leading to an altered expression of the downstream adhesion molecule, connective tissue growth factor (CTGF). In this study, we aimed to explore the interaction of possible pathways in AML-derived mesenchymal stem cells (AML-MSCs) co-cultured with the K562 and K562-ADM cell lines. AML-MSCs were co-cultured with K562/K562-ADM cells, and the interactions between the cells were verified by morphological detection, peroxidase staining (POX), reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH). The proliferation of K562/K562-ADM cells under co-culture conditions was detected by flow cytometry. The expression levels of BMP4 and CTGF were examined by RT-qPCR and western blot (WB) analysis. The detection of interleukin (IL)-6 and IL-32 was also determined by enzyme linked immunosorbent assay (ELISA). In the co-culture system, the K562-ADM cells underwent fusiform transformation. The occurrence of this transformation was associated with an increased expression of CTGF due to the dysregulation of the BMP pathway. The AML-MSCs promoted the proliferation of the K562-ADM cell, but inhibited that of the K562 cells. These findings were confirmed by changes in the expression of the soluble cytokines, IL-6 and IL-32. On the whole, the findings of this study demonstrate that AML-MSCs regulate the expression of CTGF through the BMP pathway. In addition, they affect cytokine production, induce spindle-shaped transformation, and increase drug resistance in the K562-ADM cells. Thus, the morphological transformation through the BMP pathway provides us with a novel target with which to circumvent tumor occurrence, development, drug resistance, invasion and metastasis.

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Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis

Cited by 15 publications

References 64 publications

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Immature CML cells implement a BMP autocrine loop to escape TKI treatment

AML‑derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562‑ADM fusiform transformation and chemoresistance

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