Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

Andreani, Giacomo; Carrà, Giovanna; Lingua, Marcello Francesco; Maffeo, Beatrice; Brancaccio, Mara; Taulli, Riccardo; Morotti, Alessandro

doi:10.3390/cancers12030629

Cited by 9 publications

(7 citation statements)

References 115 publications

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“…DNA methylation in mammalian cells is limited to CpG regions that usually occur in promoter areas and thereby prevents gene transcription, while gene activation is exerted by its demethylation (Figure 3; Kong et al, 2019). The methylation of the promoter area allows the regulation of differential gene expressions, and may also be involved in chronic lymphoblastic leukemia (CLL) pathogenesis (Andreani et al, 2020). The DNA methyltransferases (DNMTs), such as DNMT1, DNMT3A, DNMT3B, and DNMT3L, can methylate DNA by passing the methyl group into the cytosine pyrimidine base in 5′-CpG-3 dinucleotides (Rajabi et al, 2016).…”

Section: Epigenetic Regulation Mechanismmentioning

confidence: 99%

RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

et al. 2021

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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications.

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Section: Epigenetic Regulation Mechanismmentioning

confidence: 99%

RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

et al. 2021

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“…Besides that, it was also found that deletion on chromosome 13 at locus q14 (13q14del) also contributed to better prognosis in patients. This locus contains the coding sequence for miR-15a/16-1 cluster which target TERT suppressor p53 [108,109]. The mechanism is illustrated in Figure 3.…”

Section: Chronic Lymphoid Leukemia (Cll)mentioning

confidence: 99%

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Yik

Aziz

Rajasegaran

et al. 2021

Genes

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The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries.

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“…Chronic lymphocytic leukemia is also characterized by high levels of B-cell lymphoma 2 (BCL-2) protein, which is involved in inactivating apoptosis [14] and allowing CLL cells to evade cell death. Furthermore, loss of function of tumour suppressor genes such as TP53, ataxia telangiectasia mutated (ATM), and other somatic gene mutations (ie, SF3B-1) or complex karyotypes lead to chemotherapy-resistance in CLL [15,16]. A number of clinically approved agents have been developed to target these pathways and proteins, including acalabrutinib (BTK inhibitor), ibrutinib (BTK inhibitor), idelalisib (PI3Kδ inhibitor), obinutuzumab (anti-CD20 antibody), rituximab (anti-CD20 antibody), and venetoclax (BCL-2 inhibitor).…”

Section: First-line Treatment Evolution In the Young Fit Populationmentioning

confidence: 99%

Frontline Treatment of the Young, Fit Patient with CLL: A Canadian Perspective

2021

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From a Canadian perspective, there has been a limited discussion on the frontline management of young, fit patients with chronic lymphocytic leukemia (CLL). The prevalence of this population ranges between 2 and 22 per 100,000 persons in Canada and varies by region. Until recently, fixed-duration fludarabine-based chemoimmunotherapy (CIT) was the primary treatment option in Canada for this patient population. The ECOG1912 trial has since demonstrated that ibrutinib and rituximab therapy are as effective as fludarabine-cyclophosphamide-rituximab (FCR) in this population. The ALLIANCE trial showed that rituximab added no incremental benefit to ibrutinib. Canadian payors and physicians adopted ibrutinib monotherapy as the CLL standard of care, even in the young, fit population, although frontline ibrutinib therapy is often reimbursed by provincial public drug plans only in patients with high-risk disease or those who are unfit to receive fludarabine. Young, fit patients with CLL and their physicians may now choose between continuous ibrutinib monotherapy and fixed-duration CIT with FCR. Factors affecting this choice include patient preference and the short- and long-term toxicity profiles of both regimens, and a risk-based algorithm is provided. As new continuous-therapy options enter the market, all treatment choices present benefits and risks that must be communicated to the patient.

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Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

Cited by 9 publications

References 115 publications

RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Frontline Treatment of the Young, Fit Patient with CLL: A Canadian Perspective

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