New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism

Naka, Kazuhito

doi:10.1007/s12185-021-03112-y

Cited by 5 publications

(5 citation statements)

References 47 publications

(55 reference statements)

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“…In our CML cohort, a high FAMscore also reflected enhanced fatty acid metabolism and the rapid proliferation of malignant phenotypes of CML cells. This is because CML cells require a lot of energy and promote the fluidity of cell membranes by increasing the content of unsaturated fatty acids [ 43 ]. All these indicate that the FAMscore has certain accuracy in predicting the fatty acid metabolism activity of leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia

et al. 2022

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Background Acute myeloid leukemia (AML) is the most common malignancy of the hematological system, and there are currently a number of studies regarding abnormal alterations in energy metabolism, but fewer reports related to fatty acid metabolism (FAM) in AML. We therefore analyze the association of FAM and AML tumor development to explore targets for clinical prognosis prediction and identify those with potential therapeutic value. Methods The identification of AML patients with different fatty acid metabolism characteristics was based on a consensus clustering algorithm. The CIBERSORT algorithm was used to calculate the proportion of infiltrating immune cells. We used Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis to construct a signature for predicting the prognosis of AML patients. The Genomics of Drug Sensitivity in Cancer database was used to predict the sensitivity of patient samples in high- and low-risk score groups to different chemotherapy drugs. Results The consensus clustering approach identified three molecular subtypes of FAM that exhibited significant differences in genomic features such as immunity, metabolism, and inflammation, as well as patient prognosis. The risk-score model we constructed accurately predicted patient outcomes, with area under the receiver operating characteristic curve values of 0.870, 0.878, and 0.950 at 1, 3, and 5 years, respectively. The validation cohort also confirmed the prognostic evaluation performance of the risk score. In addition, higher risk scores were associated with stronger fatty acid metabolisms, significantly higher expression levels of immune checkpoints, and significantly increased infiltration of immunosuppressive cells. Immune functions, such as inflammation promotion, para-inflammation, and type I/II interferon responses, were also significantly activated. These results demonstrated that immunotherapy targeting immune checkpoints and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, are more suitable for patients with high-risk scores. Finally, the prediction results of chemotherapeutic drugs showed that samples in the high-risk score group had greater treatment sensitivity to four chemotherapy drugs in vitro. Conclusions The analysis of the molecular patterns of FAM effectively predicted patient prognosis and revealed various tumor microenvironment (TME) characteristics.

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Section: Discussionmentioning

confidence: 99%

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia

et al. 2022

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“…Arachidonate lipoxygenase (ALOX5)-5 and ALOX15 are also involved in LSC self-renewal and fatty acid metabolism by changing arachidonic acid to leukotrienes such as leukotriene B4 (LTB4), which increases the expression of the leukotriene B4 receptor 2 (BLT2) in CML stem cells [ 104 , 105 ]. Moreover, lysophospholipid metabolism plays a part in the maintenance of CML stem cells and TKI resistance by regulation of lysophospholipase D activity of GDPD3 in the BCR-ABL1-independent manner signaling pathway, and FOXO3A/β-catenin interaction [ 106 ].…”

Section: Survival and Functional Resistance Of CML Lscs To Therapiesmentioning

confidence: 99%

“…The inhibition of mitochondrial function has antileukemia effects along with TKIs [ 90 ]. The important findings suggest that SIRT1 and/or elements downstream in the OXPHOS pathway may be potential therapeutic targets, for instance, inhibiting PPARγ coactivator-1α (PGC-1α) by SR-18292 in combination with TKIs could avoid CML relapse by the increase in on PGC-1 acetylation levels affected of SIRT1 [ 106 ].…”

Section: Therapeutic Implications Of CML Lscsmentioning

confidence: 99%

Chronic myeloid leukemia stem cells: targeting therapeutic implications

2021

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by BCR-ABL1 oncoprotein, which plays a pivotal role in CML pathology, diagnosis, and treatment as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. Despite advances in the development of more potent tyrosine kinase inhibitors, some mechanisms particularly in terms of CML leukemic stem cell (CML LSC) lead to intrinsic or acquired therapy resistance, relapse, and disease progression. In fact, the maintenance CML LSCs in patients who are resistance to TKI therapy indicates the role of CML LSCs in resistance to therapy through survival mechanisms that are not completely dependent on BCR-ABL activity. Targeting therapeutic approaches aim to eradicate CML LSCs through characterization and targeting genetic alteration and molecular pathways involving in CML LSC survival in a favorable leukemic microenvironment and resistance to apoptosis, with the hope of providing a functional cure. In other words, it is possible to develop the combination therapy of TKs with drugs targeting genes or molecules more specifically, which is required for survival mechanisms of CML LSCs, while sparing normal HSCs for clinical benefits along with TKIs.

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“…To our surprise, enforced treatment in vitro with PGE2 restored this interaction within the nuclei of Lgr4/Gpr48 -hypomorphic mutant LT-CML stem cells, but not in Gdpd3 -deficient LT-CML stem cells (where Foxo3a was inactivated in the cytoplasm). These results suggest that Gdpd3-mediated lysophospholipid metabolism may maintain the self-renewal capacity of CML stem cells by activating the stemness factors Foxo3a and β-catenin [ 14 , 15 ].…”

Section: Biological Significance Of Gdpd3 In CML Stem Cellsmentioning

confidence: 99%

“…The question then arises: What is the factor that overcomes BCR–ABL1 and suppresses Akt activation in CML stem cells such that Foxo3a is allowed to function? Our investigation revealed that lysophospholipid metabolism inhibits Akt, and that it is the lysophospholipase D enzyme Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3) that plays an essential role in maintaining stem cell quiescence and TKI resistance in CML stem cells [ 14 , 15 ]. This involvement of lysophospholipid metabolism in CML stemness opens up a new field of investigation in the realm of novel CML treatments.…”

Section: Introductionmentioning

confidence: 99%

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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New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism

Cited by 5 publications

References 47 publications

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia

Chronic myeloid leukemia stem cells: targeting therapeutic implications

Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

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