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Molecular Genetics and Treatment of Chronic Myeloid Leukemia

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 37958

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Special Issue Editor

Dr. Masahiro Kizaki

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Guest Editor

Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Interests: hematological malignancies; chronic myeloid leukemia (CML); acute promyelocytic leukemia (APL); multiple myeloma; molecular-targeting therapy

Special Issue Information

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm that is characterized by the reciprocal translocation of chromosomes 9 and 22, namely, the Philadelphia (Ph) chromosome, forming the oncogenic BCR-ABL1 chimeric gene. The BCR-ABL1 fusion protein has constitutive tyrosine kinase (TK) activity, resulting in the proliferative advantage of stem cell and leukemia development. The introduction of TK inhibitors (TKIs) has markedly improved the clinical outcomes of CML and achieved long-term survival; thus, treatment-free remission (TFR) has now become a therapeutic goal of the disease. Recent advances in the understanding of the molecular pathogenesis of disease progression and TKI resistance in CML will contribute to the development of new concepts of therapeutic strategies. These may include eradicating CML stem cells, inhibiting other TKs, and targeting constitutively activated molecules that are located downstream of BCR-ABL1 to develop next-generation agents for CML.

In this Special Issue, we will focus on our current knowledge of the basic and clinical research progress in understanding the molecular mechanism of CML development, and the possibilities of curing the disease.

Dr. Masahiro Kizaki
Guest Editor

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Keywords

chronic myeloid leukemia (CML)
tyrosine kinase inhibitor (TKI)
treatment-free remission (TFR)
BCR-ABL1
TKI resistance
leukemic stem cell (LSC)

Published Papers (13 papers)

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Research

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18 pages, 2437 KiB

Open AccessArticle

Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia

by Yuki Fujioka, Daisuke Sugiyama, Itaru Matsumura, Yosuke Minami, Masatomo Miura, Yoshiko Atsuta, Shigeki Ohtake, Hitoshi Kiyoi, Yasushi Miyazaki, Hiroyoshi Nishikawa and Naoto Takahashi

Cancers 2021, 13(23), 5904; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235904 - 24 Nov 2021

Cited by 4 | Viewed by 2325

Abstract

Treatment-free remission (TFR) has become a therapeutic goal in chronic myeloid leukemia (CML), and approximately half of the patients with chronic phase-CML (CML-CP) with deep molecular remission (DMR) by tyrosine-kinase inhibitors (TKIs) have achieved TFR. However, the mechanism of continuous TFR is still unclear, as there are “fluctuate” patients who have BCR–ABL-positive leukemia cells but do not observe obvious relapse. We focused on the immune response and conducted an immune analysis using clinical samples from the imatinib discontinuation study, JALSG-STIM213. The results showed that, in the group that maintained TFR for 3 years, changes in regulatory T (Treg) cells were observed early after stopping imatinib treatment. The effector Treg (eTreg) cells increased transiently at 1 month after stopping imatinib and then returned to baseline at 3 months after stopping imatinib treatment. There was no difference in the Treg phenotype, and CD8⁺ T cells in the TFR group were relatively activated. High concentrations of imatinib before stopping were negatively correlated with eTreg cells after stopping imatinib. These data suggest immunological involvement in the maintenance of the TFR, and that Treg cells after stopping imatinib might be a biomarker for TFR. Furthermore, high imatinib exposure may have a negative immunological impact on the continuous TFR. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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9 pages, 669 KiB

Open AccessArticle

Droplet Digital PCR for BCR–ABL1 Monitoring in Diagnostic Routine: Ready to Start?

by Maria Teresa Bochicchio, Jessica Petiti, Paola Berchialla, Barbara Izzo, Emilia Giugliano, Emanuela Ottaviani, Santa Errichiello, Giovanna Rege-Cambrin, Claudia Venturi, Luigiana Luciano, Filomena Daraio, Daniele Calistri, Gianantonio Rosti, Giuseppe Saglio, Giovanni Martinelli, Fabrizio Pane, Daniela Cilloni, Enrico M. Gottardi and Carmen Fava

Cancers 2021, 13(21), 5470; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215470 - 30 Oct 2021

Cited by 9 | Viewed by 2148

Abstract

BCR–ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDx^TMBCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR–ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR–ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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17 pages, 4258 KiB

Open AccessArticle

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

by Toshimi Hoshiko, Yasushi Kubota, Risako Onodera, Taishi Higashi, Masako Yokoo, Keiichi Motoyama and Shinya Kimura

Cancers 2021, 13(21), 5413; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215413 - 28 Oct 2021

Cited by 8 | Viewed by 2681

Abstract

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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9 pages, 529 KiB

Open AccessArticle

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: A Study from the International Registry of Childhood CML

by Frédéric Millot, Meinolf Suttorp, Stéphanie Ragot, Guy Leverger, Jean-Hugues Dalle, Caroline Thomas, Nathalie Cheikh, Brigitte Nelken, Marilyne Poirée, Geneviève Plat, Birgitta Versluys, Birgitte Lausen and Marina Borisevich

Cancers 2021, 13(16), 4102; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164102 - 15 Aug 2021

Cited by 15 | Viewed by 2677

Abstract

Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR⁴) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR⁴ was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR⁴ for at least two years. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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12 pages, 1809 KiB

Open AccessArticle

Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia

by Richard E. Clark, Ammar A. Basabrain, Gemma M. Austin, Alison K. Holcroft, Sandra Loaiza, Jane F. Apperley, Christopher Law, Laura Scott, Alexandra D. Parry, Laura Bonnett and Claire M. Lucas

Cancers 2021, 13(9), 2155; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092155 - 29 Apr 2021

Cited by 5 | Viewed by 2972

Abstract

Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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Review

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17 pages, 1875 KiB

Open AccessReview

Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Differential Diagnosis in the WHO and ICC 2022 Era: A Focused Review

by Diletta Fontana, Elena M. Elli, Fabio Pagni and Rocco Piazza

Cancers 2023, 15(12), 3175; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15123175 - 13 Jun 2023

Cited by 2 | Viewed by 2328

Abstract

The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with SF3B1 mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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20 pages, 13586 KiB

Open AccessReview

Genomic Mechanisms Influencing Outcome in Chronic Myeloid Leukemia

by Adelina Fernandes, Naranie Shanmuganathan and Susan Branford

Cancers 2022, 14(3), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030620 - 26 Jan 2022

Cited by 9 | Viewed by 3208

Abstract

Chronic myeloid leukemia (CML) represents the disease prototype of genetically based diagnosis and management. Tyrosine kinase inhibitors (TKIs), that target the causal BCR::ABL1 fusion protein, exemplify the success of molecularly based therapy. Most patients now have long-term survival; however, TKI resistance is a persistent clinical problem. TKIs are effective in the BCR::ABL1-driven chronic phase of CML but are relatively ineffective for clinically defined advanced phases. Genomic investigation of drug resistance using next-generation sequencing for CML has lagged behind other hematological malignancies. However, emerging data show that genomic abnormalities are likely associated with suboptimal response and drug resistance. This has already been supported by the presence of BCR::ABL1 kinase domain mutations in drug resistance, which led to the development of more potent TKIs. Next-generation sequencing studies are revealing additional mutations associated with resistance. In this review, we discuss the initiating chromosomal translocation that may not always be a straightforward reciprocal event between chromosomes 9 and 22 but can sometimes be accompanied by sequence deletion, inversion, and rearrangement. These events may biologically reflect a more genomically unstable disease prone to acquire mutations. We also discuss the future role of cancer-related gene mutation analysis for risk stratification in CML. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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16 pages, 683 KiB

Open AccessReview

Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia

by Kyoko Ito and Keisuke Ito

Cancers 2021, 13(22), 5822; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225822 - 20 Nov 2021

Cited by 10 | Viewed by 2288

Abstract

Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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16 pages, 1459 KiB

Open AccessReview

Novel Treatment Strategies Utilizing Immune Reactions against Chronic Myelogenous Leukemia Stem Cells

by Maiko Matsushita

Cancers 2021, 13(21), 5435; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215435 - 29 Oct 2021

Cited by 3 | Viewed by 2335

Abstract

Introduction of tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myelogenous leukemia (CML), and treatment-free remission (TFR) is now a treatment goal. However, about half of the patients experience molecular relapse after cessation of TKIs, suggesting that leukemic stem cells (LSCs) are resistant to TKIs. Eradication of the remaining LSCs using immunotherapies including interferon-alpha, vaccinations, CAR-T cells, and other drugs would be a key strategy to achieve TFR. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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15 pages, 1163 KiB

Open AccessReview

Which Tyrosine Kinase Inhibitors Should Be Selected as the First-Line Treatment for Chronic Myelogenous Leukemia in Chronic Phase?

by Takaaki Ono

Cancers 2021, 13(20), 5116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205116 - 12 Oct 2021

Cited by 11 | Viewed by 2393

Abstract

With the use of tyrosine kinase inhibitors (TKIs), chronic myelogenous leukemia in chronic phase (CML-CP) has been transformed into a non-fatal chronic disease. Hence, “treatment-free remission (TFR)” has become a possible treatment goal of patients with CML-CP. Currently, four types of TKIs (imatinib, nilotinib, dasatinib, and bosutinib) are used as the first-line treatment for newly diagnosed CML-CP. However, the second-generation TKI (2GTKI), the treatment response of which is faster and deeper than that of imatinib, is not always recommended as the first-line treatment for CML-CP. Factors involved in TKI selection in the first-line treatment of CML-CP include not only patients’ medical background, but also patients’ choice regarding the desired treatment goal (survival or TFR?). Therefore, it is important that clinicians select an appropriate TKI to successfully achieve the desired treatment goal for each patient, while minimizing the development of adverse events. This review compares the pros and cons of using imatinib and 2GTKI for TKI selection as the first-line treatment for CML-CP, mainly considering treatment outcomes, medical history (i.e., desire for pregnancy, aging factor, and comorbidity), and cost. The optimal use of 2GTKIs is also discussed. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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19 pages, 965 KiB

Open AccessReview

Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?

by Hilbeen Hisham Saifullah and Claire Marie Lucas

Cancers 2021, 13(16), 4175; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164175 - 19 Aug 2021

Cited by 9 | Viewed by 5733

Abstract

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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18 pages, 2190 KiB

Open AccessReview

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

by Benjamin Lebecque, Céline Bourgne, Véronique Vidal and Marc G. Berger

Cancers 2021, 13(14), 3587; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143587 - 17 Jul 2021

Cited by 7 | Viewed by 3028

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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9 pages, 1290 KiB

Open AccessReview

Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

by Kazuhito Naka

Cancers 2021, 13(14), 3434; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143434 - 08 Jul 2021

Cited by 1 | Viewed by 2309

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)

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