scholarly journals Research of the Philadelphia Chromosome in Chronic Myeloid Leukemia: Diagnostic and Prognostic Interests

2021 ◽  
Author(s):  
Yahya Benbouchta ◽  
Ahmed Afailal Tribak ◽  
Khalid Sadki
Keyword(s):  
Cell Proliferation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Residual Disease ◽  
Philadelphia Chromosome ◽  
Molecular Cytogenetics ◽  
Therapeutic Monitoring ◽  
Quality Healthcare ◽  
Lymphoblastic Transformation

Myeloproliferative syndromes are cell proliferation involving one or more medullary lines without blocking maturation. Chronic myeloid leukemia (CML) is the most common of these syndromes, it corresponds to the monoclonal proliferation of a multipotent stem cell; the myeloblastic or lymphoblastic transformation of CM. has a poor prognosis. The Philadelphia chromosome t(9;22)(q34;q11) is the first cytogenetic abnormality that has been associated with a malignant process. It is found in 89 to 95% of CML. The search for the Philadelphia chromosome (Ph1) has multiple interests: Diagnostic, prognostic and in therapeutic monitoring. The search for the Philadelphia chromosome by molecular cytogenetics makes it possible to remedy the poverty of cell suspensions in metaphase to take up the inconclusive results of classic cytogenetics on nuclei in interphase and to detect residual disease during therapeutic monitoring. Through the literature review, we highlight the importance of the identification of the Philadelphia chromosome in Myeloproliferative Syndromes for the improvement of the quality healthcare of the affected patients.

scholarly journals Fluorescent in-situ hybridization (FISH) for BCR/ABL in chronic myeloid leukemia after bone marrow transplantation

2001 ◽  
Vol 119 (1) ◽  
pp. 16-18
Author(s):  
Maria de Lourdes Lopes Ferrari Chauffaille ◽  
José Salvador Rodrigues Oliveira ◽  
Maura Romeo ◽  
José Kerbauy
Keyword(s):  
Bone Marrow ◽  
In Situ Hybridization ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Fluorescent In Situ Hybridization ◽  
Residual Disease ◽  
Philadelphia Chromosome

CONTEXT: Identification of Philadelphia chromosome or BCR/ABL gene rearrangement in chronic myeloid leukemia is important at diagnosis as well as after treatment. OBJECTIVE: To compare the results of karyotyping using fluorescent in-situ hybridization (FISH) upon diagnosis and 1 year after bone marrow transplantation in 12 patients. TYPE OF STUDY: Diagnostic test and residual disease detection. SETTING: Hematology and Hemotherapy Department, Federal University of São Paulo/Escola Paulista de Medicina, São Paulo, Brazil. SAMPLE: 12 patients with chronic myeloid leukemia at diagnosis and 1 year after bone marrow transplantation. DIAGNOSTIC TEST: Karyotyping was done in the usual way and the BCR/ABL gene-specific probe was used for FISH. MAIN MEASUREMENTS: Disease at diagnosis and residual. RESULTS: At diagnosis, 10 patients presented t(9;22)(q34.1;q11) as well as positive FISH. Two cases did not have metaphases but FISH was positive. After bone marrow transplantation, 8 patients presented normal karyotype, 1 had persistence of identifiable Philadelphia chromosome and 3 had no metaphases. Two cases showed complete chimera and 2 had donor and host cells simultaneously. FISH was possible in all cases after bone marrow transplantation and confirmed the persistence of identifiable Philadelphia chromosome clone in one patient, and identified another that did not present metaphases for analysis. Cases that showed mixed chimera in karyotype were negative for BCR/ABL by FISH. CONCLUSION: The applicability of FISH is clear, particularly for residual disease detection. Classical and molecular cytogenetics are complementary methods.

scholarly journals A new highly sensitive real-time quantitative-PCR method for detection of BCR-ABL1 to monitor minimal residual disease in chronic myeloid leukemia after discontinuation of imatinib

2018 ◽  
Author(s):  
Hiroaki Kitamura ◽  
Yoko Tabe ◽  
Koji Tsuchiya ◽  
Maiko Yuri ◽  
Tomohiko Ai ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real Time ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Pcr Method ◽  
Minimal Residual

AbstractTyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion protein, encoded by the Philadelphia chromosome, have drastically improved the outcomes for patients with chronic myeloid leukemia (CML). Although several real-time quantitative polymerase chain reaction (RQ-PCR) kits for the detection of BCR-ABL1 transcripts are commercially available, their accuracy and efficiency in laboratory practice require reevaluation. We have developed a new in-house RQ-PCR method to detect minimal residual disease (MRD) in CML cases. MRD was analyzed in 102 patients with CML from the DOMEST study, a clinical trial to study the rationale for imatinib mesylate discontinuation in Japan. The BCR-ABL1/ABL1 ratio was evaluated using the international standard (IS) ratio, where IS < 0.01% was defined as a major molecular response. At enrollment, BCR-ABL1 transcripts were undetectable in all samples using a widely-applied RQ-PCR method performed in the commercial laboratory, BML (BML Inc., Tokyo, Japan); however, the in-house method detected the BCR-ABL1 transcripts in five samples (5%) (mean IS ratio: 0.0062 ± 0.0010%). After discontinuation of imatinib, BCR-ABL1 transcripts were detected using the in-house RQ-PCR in 21 patients (21%) that were not positive using the BML method. Nineteen samples were also tested using a commercially available RQ-PCR assay kit with a detection limit of IS ratio, 0.0007% (ODK-1201, Otsuka Pharmaceutical Co., Tokyo, Japan). This method detected low levels of BCR-ABL1 transcripts in 14 samples (74%), but scored negative for five samples (26%) that were positive using the in-house method. These data suggest that our new in-house RQ-PCR method is effective for monitoring MRD in CML.

THE CASE VARIANT TRANSLOCATION T(3;9;22)(P24;Q34;Q11) IN CHRONIC MYELOID LEUKEMIA

2018 ◽  
Vol 64 (6) ◽  
pp. 810-814
Author(s):  
Kodirzhon Boboev ◽  
Yuliana Assesorova ◽  
Kh. Karimov ◽  
B. Allanazarova
Keyword(s):  
Adverse Effect ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Genetic Locus ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Banding Technique ◽  
Variant Translocation

This paper presents a case of chronic myeloid leukemia with an earlier unknown variant translocation t (3; 9; 22) (p24; q34; q11) detected by cytogenetic research using the GTG-banding technique. Despite the absence of the classical Philadelphia chromosome, the presence of chromosome 9 and 22 derivatives, as well as the BCR-ABL fusion gene, allow this translocation to be considered pathogenetic for CML. A good response of the patient to the treatment with glivec is that there is no adverse effect on the pathogenesis of the disease of an additional genetic locus (3p24) involved in complex restructuring.

Effect of Dasatinib on Genes Related to Mitotic Catastrophe Pathway in Chronic Myeloid Leukemia Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Sezgi Kipcak ◽  
Buket Ozel ◽  
Cigir B. Avci ◽  
Leila S. Takanlou ◽  
Maryam S. Takanlou ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Mitotic Catastrophe ◽  
Control Group ◽  
Cancer Therapies ◽  
Apoptosis Pathways

Background: Chronic myeloid leukemia (CML), is characterized by a reciprocal translocation t(9;22) and forms the BCR/ABL1 fusion gene, which is called the Philadelphia chromosome. The therapeutic targets for CML patients which are mediated with BCR/ABL1 oncogenic are tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib. The latter two of which have been approved for the treatment of imatinib-resistant or intolerance CML patients. Mitotic catastrophe (MC) is one of the non-apoptotic mechanisms which frequently initiated in types of cancer cells in response to anti-cancer therapies; pharmacological inhibitors of G2 checkpoint members or genetic suppression of PLK1, PLK2, ATR, ATM, CHK1, and CHK2 can trigger DNA-damage-stimulated mitotic catastrophe. PLK1, AURKA/B anomalously expressed in CML cells, that phosphorylation and activation of PLK1 occur by AURKB at centromeres and kinetochores. Objective: The purpose of this study was to investigate the effect of dasatinib on the expression of genes in MC and apoptosis pathways in K562 cells. Methods: Total RNA was isolated from K-562 cells treated with the IC50 value of dasatinib and untreated cells as a control group. The expression of MC and apoptosis-related genes were analyzed by the qRT-PCR system. Results: The array-data demonstrated that dasatinib-treated K562 cells significantly caused the decrease of several genes (AURKA, AURKB, PLK, CHEK1, MYC, XPC, BCL2, and XRCC2). Conclusion: The evidence supply a basis to support clinical researches for the suppression of oncogenes such as PLKs with AURKs in the treatment of types of cancer especially chronic myeloid leukemia.

scholarly journals Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network

2021 ◽  
Author(s):  
Vivien Schäfer ◽  
Helen E. White ◽  
Gareth Gerrard ◽  
Susanne Möbius ◽  
Susanne Saussele ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
False Negative ◽  
Patient Specific ◽  
Molecular Response ◽  
Real Time Quantitative Pcr ◽  
Log Reduction ◽  
Negative Results ◽  
False Negative Results

Abstract Purpose Approximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. Methods BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). Results In total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Conclusions Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.

scholarly journals Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 445
Author(s):  
Daniela Zizioli ◽  
Simona Bernardi ◽  
Marco Varinelli ◽  
Mirko Farina ◽  
Luca Mignani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Transgenic Zebrafish ◽  
Hematopoietic Tissue ◽  
Zebrafish Model ◽  
Altered Expression

Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.

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