On the Power of Additional and Complex Chromosomal Aberrations in CML

Greulich-Bode, Karin M.; Heinze, B

doi:10.2174/138920212802510466

Cited by 10 publications

(6 citation statements)

References 37 publications

(47 reference statements)

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“…Until now, only few BCR-ABL1-independent genetic lesions (for example, c-Myc copy number gain, RB1 mutations) are known to be involved in CML progression. 2, 3, 4 The potential contribution of epigenetic changes, especially of DNA methylation (referred to as methylation) to CML progression, has not been investigated in detail so far. 5, 6, 7 …”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia

et al. 2016

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Little is known about the impact of DNA methylation on the evolution/progression of Ph+ chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. Although only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared with controls, ~6500 differentially methylated CpG sites were found in samples from BC-CML patients. In the majority of affected CpG sites, methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes that were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared with CP-CML samples. Several of them are well-known tumor-suppressor genes or regulators of cell proliferation, and gene re-expression was observed by the use of epigenetic active drugs. Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML.

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Section: Introductionmentioning

confidence: 99%

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia

et al. 2016

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“…The main gene responsible for cell proliferation and survival in CP-CML patients is BCR-ABL fusion gene. Only few BCR-ABL independent genetic mutations are known in CML progression (22).…”

Section: E J M Rmentioning

confidence: 99%

A Comprehensive Review on the Role of Cell Growth and Apoptotic Genes Towards the Progression of CML

Fatima¹,

Mahdi²,

Afreen³

et al. 2019

EJMR

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Imatinib is a tyrosin kinase inhibitor, which has proven to be very effective in achieving high remission rates and improving prediction of treatment outcome. However a fraction of CML patients presents with resistance to this drug. Imatinib-based therapies were discontinued due to resistance and intolerance/noncompliance. the resistance for imatinib is developed due to the occurrence of point mutations in the BCR-ABL KD(kinase domain), although BCR-ABL amplification and impaired signaling pathways may contribute to the resistance. Other possible BCR-ABL independent mechanisms that influence resistance include reduced bioavailability of imatinib within Ph-positive cells, cytogenetic changes, disfunctionality of p53, and activation of alternative signaling pathways that promote cell survival and proliferation and reduced apoptosis. The achievement of Chronic myeloid leukemia (CML) is one of the most common leukemia. CML is described by a balanced genetic translocation, t(9;22)(q34;q11.2), in which the Abelson gene (ABL1) from chromosome 9q34 fused with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This genetic translocation is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein , which is the type of protein called a tyrosine kinase. This protein causes CML cells to grow and divide out of control. In a very small number of CML cases, the leukemia cells have the BCR-ABL oncogene but not the Philadelphia chromosome. It's thought that the BCR-ABL gene must form in a different way in these people. In an even smaller number of people who seem to have CML, neither the Philadelphia chromosome nor the BCR-ABL oncogene can be found. They might have other, unknown oncogenes causing their disease and are not considered to truly have CML.

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“…Most of the patients present in CP [4][5]. Generally, chronic phase is characterized by leukocytosis, anemia and splenomegaly with detection of BCR-ABL fusion gene [6]. Blastic crisis is essentially like acute leukemia and is chemo refractory with a median survival of 3 to 6 months [7].…”

Section: Introductionmentioning

confidence: 99%

Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

Maqsood

Ali

Hameed³

et al. 2021

Asian Pac J Cancer Care

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Background and Purpose: Chronic Myeloid Leukemia (CML) is a common hematological malignancy. The characteristic molecular abnormality is the presence of Philadelphia chromosome or BCR-ABL fusion gene which is the result of 9:22 translocation. Tyrosine kinase inhibitors (TKIs) form the main stay of treatment in CML with excellent responses. The purpose of this study was to determine the impact of additional chromosomal abnormalities on outcomes in CML.Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results: A total of 283 patients were diagnosed with CML from January 2010 to January 2015. 31 patients out of these were found to have additional chromosomal abnormalities at the time of diagnosis in addition to BCR-ABL fusion gene or Philadelphia chromosome detection. Out of these 31 patients, 23 (74.2%) were males whereas 8 (25.8%) were females. 13 (41.9%) were in the age group of 31 to 50 years whereas the other two groups that is 18 to 30 years and 51 to 70 years had 9 patients each. After approval from the government which usually takes a standard 2-3 weeks’ time, these patients were started on tyrosine kinase inhibitors which was Imatinib in 30 (96.8%) and Nilotinib in 1 (3.2%) patient. Conventional cytogenetic analysis performed for each patient at the time of diagnosis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. 2 patents each had isochrome 17q, inversion 3 and deletion 9 abnormalities. 1 patient had deletion 7 whereas 1 had variant Philadelphia chromosome with other chromosomal abnormalities. Conclusion: It was evident that frequently occurring ACAs In our CML population were Variant Philadelphia chromosome and trisomy 8.

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On the Power of Additional and Complex Chromosomal Aberrations in CML

Cited by 10 publications

References 37 publications

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia

A Comprehensive Review on the Role of Cell Growth and Apoptotic Genes Towards the Progression of CML

Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

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