Inhibition of Ras-mediated signaling pathways in CML stem cells

Several factors such as chromosomal translocations, gene mutations, and polymorphisms are involved in the pathogenesis of leukemia/lymphoma. Recently, the role of vitamin D (VD) and vitamin D receptor (VDR) polymorphisms in hematologic malignancies has been considered. In this review, we examine the possible role of VD levels, as well as VDR polymorphisms as prognostic biomarkers in leukemia/lymphoma. Relevant English language literature were searched and retrieved from Google Scholar search engine (1985-2017). The following keywords were used: vitamin D, vitamin D receptor, leukemia, lymphoma, and polymorphism. Increased serum levels of VD in patients with leukemia are associated with a better prognosis. However, low VD levels are associated with a poor prognosis, and VDR polymorphisms in various leukemias can have prognostic value. VD biomarker can be regarded as a potential prognostic factor for a number of leukemias, including acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL). There is a significant relationship between different polymorphisms of VDR (including Taq I and Fok I) with several leukemia types such as ALL and AML, which may have prognostic value.

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“… 17 MAPK pathway has been recognized as one of the most important pathways involved in the development of cancers, especially leukemias. 18 …”

Section: Vitamin D and Gene Regulationmentioning

confidence: 99%

Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias

et al. 2018

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“…A recent assessment of CML mouse models and patient-derived stem cells has revealed that CML-derived stem cells may not be dependent on the presence of BCR-ABL for their survival. These data suggest that therapeutic approaches should also be aimed at targeting BCR-ABL independent mechanisms governing LSC resistance and survival [158, 159]. …”

Section: Targeting Leukemia Stem Cellsmentioning

confidence: 99%

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

et al. 2016

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Background Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens. Conclusions A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy.

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“…19 Activating mutations or Ras gene amplification is observed in nearly a third of human cancers. 20 These mutations lead to non-ligand-dependent activation of signaling pathways, leading to increased cell proliferation. Mutations involving Ras gene mutations, most notably NRAS, are observed in 5-10% of MDS patients; however, the prevalence of this mutation is up to 30% in patients with isolated isochromosome 17 [i (17q)].…”

Section: Genetic and Epigenetic Abnormalitiesmentioning

confidence: 99%

Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights

Shahrabi¹,

Khosravi²,

Shahjahani³

et al. 2016

Oncol Rev

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Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied. The most common molecular abnormalities were TET2, ASXL1 as well as molecules involved in spliceosome machinery (U2AF1, SRSF2 and SF3B1). Patients with defects in TET2 molecule show better response to treatment with azacitidine. IDH and DNMT3A mutations are associated with a good response to decitabine therapy. In addition, patients with del5q subtype harboring TP53 mutation do not show a good response to lenalidomide therapy.In general, the results of this study show that molecular abnormalities can be associated with the occurrence of a specific morphological phenotype in patients. Therefore, considering the morphology of patients, different gene profiling methods can be selected to choice the most appropriate therapeutic measure in these patients in addition to faster and more cost-effective diagnosis of molecular abnormalities.

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Inhibition of Ras-mediated signaling pathways in CML stem cells

Abstract: A closer investigation of the influence of Ras-mediated signaling pathways on CML progression to blast crisis is warranted to uncover new directions for targeted therapies, particularly in cases that are resistant to current tyrosine kinase inhibitors.

Cited by 15 publications

References 104 publications

Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias

Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights

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