Dnmt1 links BCR-ABLp210 to epigenetic tumor stem cell priming in myeloid leukemia

Vicente-Dueñas, Carolina; González-Herrero, Inés; Sehgal, Lalit; García-Ramírez, Idoia; Rodríguez-Hernández, Guillermo; Pintado, B.; Blanco, Óscar; Criado, Francisco Javier García; Cenador, María Begoña García; Green, Michael R.; Sánchez-Garcı́a, Isidro

doi:10.1038/s41375-018-0192-z

Cited by 20 publications

(24 citation statements)

References 15 publications

(17 reference statements)

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“…Sánchez-Garcia and colleagues have argued that restriction of a leukemic HSC to one pathway occurs by oncogenes orchestrating the epigenome toward a leukemic cell lineage – with additional oncogene insults then converting this cell into a leukemia stem cell (LSC). Activity of the first oncogene is neither necessary to maintain LSCs nor for disease progression (Brown and Sanchez-Garcia, 2015; García-Ramírez et al, 2018; Vicente-Dueñas et al, 2018; Vicente-Dueñas et al, 2019). Its role is to focus HSC options into only one pathway, thus restricting LSCs and their progeny to that pathway.…”

Section: Implications For Leukemiamentioning

confidence: 99%

Modeling the Hematopoietic Landscape

Brown

Ceredig

2019

Front. Cell Dev. Biol.

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Some time ago, we proposed a continuum-like view of the lineages open to hematopoietic stem cells (HSCs); each HSC self-renews or chooses from the spectrum of all end-cell options and can then "merely" differentiate. Having selected a cell lineage, an individual HSC may still "step sideways" to an alternative, albeit closely related, fate: HSC and their progeny therefore remain versatile. The hematopoietic cytokines erythropoietin, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and ligand for the fms-like tyrosine kinase 3 instruct cell lineage. Sub-populations of HSCs express each of the cytokine receptors that are positively auto-regulated upon cytokine binding. Many years ago, Waddington proposed that the epigenetic landscape played an important role in cell lineage choice. This landscape is dynamic and unstable especially regarding DNA methylation patterns across genomic DNA. This may underlie the receptor diversity of HSC and their decision-making.

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Section: Implications For Leukemiamentioning

confidence: 99%

Modeling the Hematopoietic Landscape

Brown

Ceredig

2019

Front. Cell Dev. Biol.

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“…affiliation either throughout or at a particular stage of LSC development, thus restricting the leukaemic cells to that pathway ( Figure 1) [30]. This may occur via the oncogene-mediated priming of the epigenome in cells to adopt a single cell lineage [29,30]. While we argue that specific oncogenes/genomic insults to HSCs give rise to a particular lineagerestricted type of leukaemia, there are some caveats to extending this assertion to other types of cancer.…”

Section: Leukaemic Cells Belong To One Lineagementioning

confidence: 77%

“…The BCR-ABL p190 , LMO2, and BCR-ABL p210 oncogenes play a role in human B-lymphocyte, acute T-lymphoblastic, and chronic myeloid leukaemia, respectively. In transgenic mice in which the expression of BCR-ABL p190 , LMO2, and BCR-ABL p210 was restricted to HSCs via the Sca-1 promotor, carcinogenesis was initiated by the oncogenes, and the resultant cancer recapitulated lineage-restricted human disease [27][28][29]. In transgenic mice, the oncogene is solely active within LICs/LSCs and is therefore not essential for the survival and/or proliferation of more mature lineage-affiliated leukaemic cells.…”

Section: Leukaemic Cells Belong To One Lineagementioning

confidence: 99%

“…An interpretation of these findings is that the oncogene 'hardwires' lineage affiliation either throughout or at a particular stage of LSC development, thus restricting the leukaemic cells to that pathway ( Figure 1) [30]. This may occur via the oncogene-mediated priming of the epigenome in cells to adopt a single cell lineage [29,30]. affiliation either throughout or at a particular stage of LSC development, thus restricting the leukaemic cells to that pathway ( Figure 1) [30].…”

Section: Leukaemic Cells Belong To One Lineagementioning

confidence: 99%

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Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

Brown

Sánchez

Sánchez-Garcı́a

2019

IJMS

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Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These ‘hits’ do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2, associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This ‘hardwiring’ of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.

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“…In order to compare the maximum cell inducing effect of BH3-mimetics irrespective of dose, all compounds were used at 1 µM. This concentration was selected based on previous results obtained from in vitro differentiated basophils 9 and on other studies demonstrating that 1 µM does not induce cellular toxicity 10 . We confirmed that specific inhibition of BCL-2 by ABT-199 during 8 hours elicited a significant decrease in human and mouse B cell numbers, whereby the effect was more pronounced in human B cells (compare Fig.…”

Section: Resultsmentioning

confidence: 99%

Impact of BH3-mimetics on Human and Mouse Blood Leukocytes: A Comparative Study

Rohner

Reinhart

Iype

et al. 2020

Sci Rep

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BH3-mimetics are small molecule inhibitors that neutralize the function of anti-apoptotic BCL-2 family members. BH3-mimetics have recently gained a lot of popularity in oncology because of their success in cancer treatment. However, BH3-mimetics might have a broader clinical application. Here, we established an ex vivo flow cytometric assay allowing the comparison of the impact of BH3-mimetics (ABT-199, ABT-263, WEHI-539, and S63845) on leukocyte populations of both, healthy human subjects and C57BL/6 J wild type mice. BH3-mimetics were added to freshly drawn blood that was diluted 1/2 in cell medium, and BH3-mimetics-mediated impact on leukocyte count was assessed by flow cytometry. Our results demonstrate that responses towards 1μM of BH3-mimetics can be identical as well as considerably different in leukocytes of humans and mice. For instance, the inhibition of BCL-2 by ABT-199 caused cell death in all types of lymphocytes in mice but was exclusively specific for B cells in humans. Moreover, inhibition of BCL-X L by WEHI-539 affected solely mouse leukocytes while targeting MCL-1 by S63845 resulted in efficient induction of cell death in human neutrophils but not in their mouse counterparts. Our ex vivo assay enables initial identification of analogies and differences between human and mouse leukocytes in response towards BH3-mimetics. Excessive cell death or evasion from apoptosis is associated with the development of autoimmune disorders or cancer 1. Apoptosis is primarily regulated by B cell lymphoma 2 (BCL-2) family members, which differ based on their ability to promote or to suppress apoptosis by affecting the integrity of the mitochondrial outer membrane (MOM). Anti-apoptotic BCL-2 family members (BCL-2, BCL-X L , BCL-W, MCL-1, BFL-1/A1) function by inhibiting their pro-apoptotic counterparts, which, upon their "unleashing", trigger MOM permeabilization followed by activation of apoptotic caspases, culminating in the ultimate, irreversible cascade towards cellular demise 2,3. Previous studies have shown that the interplay of pro-and anti-apoptotic BCL-2 members specifically regulates hematopoiesis and survival of leukocytes in blood and bone marrow 4,5. Importantly, upregulation of certain anti-apoptotic BCL-2 family members, such as BCL-2, B cell lymphoma-extra-large (BCL-X L), and myeloid cell leukemia (MCL-1), are also known to support development and survival of cancerous cells as well as evasion from cancer therapy 6. To overcome such resistance towards apoptosis, small molecule inhibitors called BCL-2 homology domain 3 (BH3)-mimetics have been developed to specifically neutralize anti-apoptotic BCL-2 family members in order to restore normal apoptotic signaling in cancerous cells 7. Most studies involving BH3-mimetics have been carried out in cancer cells. However, with some exceptions, the impact of these compounds on key leukocyte populations from healthy individuals is less clear. As the expression of individual anti-apoptotic BCL-2 family members varies substantially between different leukocyte...

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Dnmt1 links BCR-ABLp210 to epigenetic tumor stem cell priming in myeloid leukemia

Cited by 20 publications

References 15 publications

Modeling the Hematopoietic Landscape

Modeling the Hematopoietic Landscape

Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

Impact of BH3-mimetics on Human and Mouse Blood Leukocytes: A Comparative Study

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