Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

Minciacchi, Valentina R.; Kumar, Rahul; Krause, Daniela

doi:10.3390/cells10010117

Cited by 106 publications

(89 citation statements)

References 192 publications

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“…CML is a malignant myeloproliferative disorder characterized by clonal hematopoietic stem cell proliferation [176]. CML is the BCR-ABL1 oncoprotein-positive MPN characterized by the Philadelphia (Ph) chromosome's presence.…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

Kapor

Santibanez

2021

JCM

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Myeloid malignancies arise from an altered hematopoietic stem cell and mainly comprise acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic leukemic cells may influence the growth and differentiation of other hematopoietic cell lineages in peripheral blood and bone marrow. Myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs) display immunoregulatory properties by controlling the innate and adaptive immune systems that may induce a tolerant and supportive microenvironment for neoplasm development. This review analyzes the main features of MDSCs and MSCs in myeloid malignancies. The number of MDSCs is elevated in myeloid malignancies exhibiting high immunosuppressive capacities, whereas MSCs, in addition to their immunosuppression contribution, regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance. Moreover, MSCs may promote MDSC expansion, which may mutually contribute to the creation of an immuno-tolerant neoplasm microenvironment. Understanding the implication of MDSCs and MSCs in myeloid malignancies may favor their potential use in immunotherapeutic strategies.

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Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

Kapor

Santibanez

2021

JCM

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“…It turns out that the CML stem cells that generate most mature CML cells are responsible for disease relapse post-TKI therapy [ 6 , 7 , 8 ]. While mature CML cells actively proliferate due to BCR–ABL1-dependent signaling, CML stem cells are able to avoid proliferation and maintain quiescence in an oncogene-independent fashion [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…To date, much research effort has been devoted to investigating the molecular mechanisms by which CML stem cells exploit stem cell quiescence, and searching for new modes of therapy that can be combined with TKI therapy to eradicate not only mature CML cells but also CML stem cells. Many researchers reported that numerous molecular mechanisms regulate the quiescence and TKI resistance in CML stem cells in vivo [ 6 , 7 , 8 ]. It is reportedly known that several factors within the bone marrow microenvironmental niche are also responsible for the maintenance of self-renewal capacity in CML stem cells in a non-cell autonomous manner [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Many researchers reported that numerous molecular mechanisms regulate the quiescence and TKI resistance in CML stem cells in vivo [ 6 , 7 , 8 ]. It is reportedly known that several factors within the bone marrow microenvironmental niche are also responsible for the maintenance of self-renewal capacity in CML stem cells in a non-cell autonomous manner [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

Naka

2021

Cancers

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It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR–ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.

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“…BCR-ABL-related resistance mechanisms, such as point mutations, explain only a minority of the cases of primary resistance to TKIs [ 5 ], but are representative examples of intra-clonal heterogeneity because cells harboring a BCR-ABL mutation are mostly selected by targeted therapy [ 12 ]. Other BCR-ABL-independent mechanisms have been suggested, for example related to the microenvironment [ 13 , 14 ]. Similar to many other cancer types, epigenetic abnormalities also could be involved, notably DNA methylation [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

Lebecque

Bourgne

Vidal³

et al. 2021

Cancers

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Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.

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Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

Cited by 106 publications

References 192 publications

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

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