ISODERIVATIVE PHILADELPHIA CHROMOSOME IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Lukyanova A. 06/09/16; 134708; PB1808
Anna Lukyanova
Contributions
Contributions
Abstract
Abstract: PB1808
Type: Publication Only
Background
The key point in pathogenesis of chronic myeloid leukemia (CML) is occurrence of Philadelphia chromosome as a result of reciprocal translocation of chromosomes 9 and 22 leading to formation of the BCR-ABL fusion gene. Increasing number of copies of this oncogene may be one of the reasons for disease progression and lack of response to treatment with tyrosine kinase inhibitors. Usually, this process develops due to occurrence of additional copies of the Ph-chromosome without alteration of its structure. This report however describes 5 cases of changed morphology of derivative chromosome 22 (particularly isochromosome 22), leading to increased number of BCR-ABL gene copies. Despite the fact that occurrence of an isochromosome can be quite frequent in various malignancies reports concerning isoderivative chromosome 22 are quite rare.
Aims
The aim of this study was an attempt to establish the mechanisms leading to modifications of derivative 22 structure; and to investigate the number of BCR-ABL gene copies and its localization.
Methods
Methods of conventional cytogenetics (karyotyping of bone marrow cells) and FISH using BCR-ABL DC DF probe (Vysis) were applied.
Results
Cytogenetic aberrations involving increased numbers of copies of Ph-chromosome and BCR-ABL gene were detected in 30 patients overall. Occurrence of 1 or more additional Ph-chromosomes without structural changes was found in 25 of the cases. Structural modifications of derivative chromosome 22 were revealed in 5 patients. Evidences of isoderivative chromosome 22 were found in 4 of them in amount of 1-2 copies per metaphase plate, whereas in 1 case dicentric isoderivative chromosome 22 was detected in amount of 1-5 copies per metaphase plate (Fig. 1). Presence of two copies of BCR-ABL on both arms of isoderivative 22 in all cases was confirmed by FISH on metaphase plates. It was hence proved that the detected isoderivative 22 in these 4 patients was composed of the long arms of Ph-chromosome with fragments of chromosome 22 and 9 linked by centromere of chromosome 22. Presence of two copies of BCR-ABL was also confirmed by FISH for the patient with dicentric isoderivative chromosome 22. However, in this case the isoderivative comprised two cetromeres of chromosome 22 and the long arms were connected by telomeric areas of the translocated fragments of chromosome 9. Total number of BCR-ABL copies in cells with isoderivative was 2-10.The described abnormalities were detected in 4 patients treated with imatinib. Therapy was subsequently changed to nilotinib in 3 of them and to dasatinib in 1 patient. After switching to nilotinib cytogenetic response was not achieved in 2 patients who subsequently died of disease progression. In case of dasatinib the patient also failed to reach cytogenetic response. Only in one patient after 2 years of nilotinib complete cytogenetic response (CCyR) was obtained. In remaining 5th patient who failed after 1 year of imatinib without any clonal evolution treatment was changed to nilotinib. After 6 months of this treatment CCyR was achieved, however after 12 months occurrence of isoderivative 22 was for the first time detected in 50% of the cells. The patient currently continues being followed.
Conclusion
The paper describes 5 cases of rare structural modifications of derivative chromosome 22, leading to increased numbers of copies of BCR-ABL gene. In majority of these cases patients were resistant to treatment with tyrosine kinase inhibitors. Detected aberrations most probably represent one of the mechanisms of the secondary resistance and disease progression in CML.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Cytogenetic abnormalities, Ph chromosome
Type: Publication Only
Background
The key point in pathogenesis of chronic myeloid leukemia (CML) is occurrence of Philadelphia chromosome as a result of reciprocal translocation of chromosomes 9 and 22 leading to formation of the BCR-ABL fusion gene. Increasing number of copies of this oncogene may be one of the reasons for disease progression and lack of response to treatment with tyrosine kinase inhibitors. Usually, this process develops due to occurrence of additional copies of the Ph-chromosome without alteration of its structure. This report however describes 5 cases of changed morphology of derivative chromosome 22 (particularly isochromosome 22), leading to increased number of BCR-ABL gene copies. Despite the fact that occurrence of an isochromosome can be quite frequent in various malignancies reports concerning isoderivative chromosome 22 are quite rare.
Aims
The aim of this study was an attempt to establish the mechanisms leading to modifications of derivative 22 structure; and to investigate the number of BCR-ABL gene copies and its localization.
Methods
Methods of conventional cytogenetics (karyotyping of bone marrow cells) and FISH using BCR-ABL DC DF probe (Vysis) were applied.
Results
Cytogenetic aberrations involving increased numbers of copies of Ph-chromosome and BCR-ABL gene were detected in 30 patients overall. Occurrence of 1 or more additional Ph-chromosomes without structural changes was found in 25 of the cases. Structural modifications of derivative chromosome 22 were revealed in 5 patients. Evidences of isoderivative chromosome 22 were found in 4 of them in amount of 1-2 copies per metaphase plate, whereas in 1 case dicentric isoderivative chromosome 22 was detected in amount of 1-5 copies per metaphase plate (Fig. 1). Presence of two copies of BCR-ABL on both arms of isoderivative 22 in all cases was confirmed by FISH on metaphase plates. It was hence proved that the detected isoderivative 22 in these 4 patients was composed of the long arms of Ph-chromosome with fragments of chromosome 22 and 9 linked by centromere of chromosome 22. Presence of two copies of BCR-ABL was also confirmed by FISH for the patient with dicentric isoderivative chromosome 22. However, in this case the isoderivative comprised two cetromeres of chromosome 22 and the long arms were connected by telomeric areas of the translocated fragments of chromosome 9. Total number of BCR-ABL copies in cells with isoderivative was 2-10.The described abnormalities were detected in 4 patients treated with imatinib. Therapy was subsequently changed to nilotinib in 3 of them and to dasatinib in 1 patient. After switching to nilotinib cytogenetic response was not achieved in 2 patients who subsequently died of disease progression. In case of dasatinib the patient also failed to reach cytogenetic response. Only in one patient after 2 years of nilotinib complete cytogenetic response (CCyR) was obtained. In remaining 5th patient who failed after 1 year of imatinib without any clonal evolution treatment was changed to nilotinib. After 6 months of this treatment CCyR was achieved, however after 12 months occurrence of isoderivative 22 was for the first time detected in 50% of the cells. The patient currently continues being followed.
Conclusion
The paper describes 5 cases of rare structural modifications of derivative chromosome 22, leading to increased numbers of copies of BCR-ABL gene. In majority of these cases patients were resistant to treatment with tyrosine kinase inhibitors. Detected aberrations most probably represent one of the mechanisms of the secondary resistance and disease progression in CML.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Cytogenetic abnormalities, Ph chromosome
Abstract: PB1808
Type: Publication Only
Background
The key point in pathogenesis of chronic myeloid leukemia (CML) is occurrence of Philadelphia chromosome as a result of reciprocal translocation of chromosomes 9 and 22 leading to formation of the BCR-ABL fusion gene. Increasing number of copies of this oncogene may be one of the reasons for disease progression and lack of response to treatment with tyrosine kinase inhibitors. Usually, this process develops due to occurrence of additional copies of the Ph-chromosome without alteration of its structure. This report however describes 5 cases of changed morphology of derivative chromosome 22 (particularly isochromosome 22), leading to increased number of BCR-ABL gene copies. Despite the fact that occurrence of an isochromosome can be quite frequent in various malignancies reports concerning isoderivative chromosome 22 are quite rare.
Aims
The aim of this study was an attempt to establish the mechanisms leading to modifications of derivative 22 structure; and to investigate the number of BCR-ABL gene copies and its localization.
Methods
Methods of conventional cytogenetics (karyotyping of bone marrow cells) and FISH using BCR-ABL DC DF probe (Vysis) were applied.
Results
Cytogenetic aberrations involving increased numbers of copies of Ph-chromosome and BCR-ABL gene were detected in 30 patients overall. Occurrence of 1 or more additional Ph-chromosomes without structural changes was found in 25 of the cases. Structural modifications of derivative chromosome 22 were revealed in 5 patients. Evidences of isoderivative chromosome 22 were found in 4 of them in amount of 1-2 copies per metaphase plate, whereas in 1 case dicentric isoderivative chromosome 22 was detected in amount of 1-5 copies per metaphase plate (Fig. 1). Presence of two copies of BCR-ABL on both arms of isoderivative 22 in all cases was confirmed by FISH on metaphase plates. It was hence proved that the detected isoderivative 22 in these 4 patients was composed of the long arms of Ph-chromosome with fragments of chromosome 22 and 9 linked by centromere of chromosome 22. Presence of two copies of BCR-ABL was also confirmed by FISH for the patient with dicentric isoderivative chromosome 22. However, in this case the isoderivative comprised two cetromeres of chromosome 22 and the long arms were connected by telomeric areas of the translocated fragments of chromosome 9. Total number of BCR-ABL copies in cells with isoderivative was 2-10.The described abnormalities were detected in 4 patients treated with imatinib. Therapy was subsequently changed to nilotinib in 3 of them and to dasatinib in 1 patient. After switching to nilotinib cytogenetic response was not achieved in 2 patients who subsequently died of disease progression. In case of dasatinib the patient also failed to reach cytogenetic response. Only in one patient after 2 years of nilotinib complete cytogenetic response (CCyR) was obtained. In remaining 5th patient who failed after 1 year of imatinib without any clonal evolution treatment was changed to nilotinib. After 6 months of this treatment CCyR was achieved, however after 12 months occurrence of isoderivative 22 was for the first time detected in 50% of the cells. The patient currently continues being followed.
Conclusion
The paper describes 5 cases of rare structural modifications of derivative chromosome 22, leading to increased numbers of copies of BCR-ABL gene. In majority of these cases patients were resistant to treatment with tyrosine kinase inhibitors. Detected aberrations most probably represent one of the mechanisms of the secondary resistance and disease progression in CML.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Cytogenetic abnormalities, Ph chromosome
Type: Publication Only
Background
The key point in pathogenesis of chronic myeloid leukemia (CML) is occurrence of Philadelphia chromosome as a result of reciprocal translocation of chromosomes 9 and 22 leading to formation of the BCR-ABL fusion gene. Increasing number of copies of this oncogene may be one of the reasons for disease progression and lack of response to treatment with tyrosine kinase inhibitors. Usually, this process develops due to occurrence of additional copies of the Ph-chromosome without alteration of its structure. This report however describes 5 cases of changed morphology of derivative chromosome 22 (particularly isochromosome 22), leading to increased number of BCR-ABL gene copies. Despite the fact that occurrence of an isochromosome can be quite frequent in various malignancies reports concerning isoderivative chromosome 22 are quite rare.
Aims
The aim of this study was an attempt to establish the mechanisms leading to modifications of derivative 22 structure; and to investigate the number of BCR-ABL gene copies and its localization.
Methods
Methods of conventional cytogenetics (karyotyping of bone marrow cells) and FISH using BCR-ABL DC DF probe (Vysis) were applied.
Results
Cytogenetic aberrations involving increased numbers of copies of Ph-chromosome and BCR-ABL gene were detected in 30 patients overall. Occurrence of 1 or more additional Ph-chromosomes without structural changes was found in 25 of the cases. Structural modifications of derivative chromosome 22 were revealed in 5 patients. Evidences of isoderivative chromosome 22 were found in 4 of them in amount of 1-2 copies per metaphase plate, whereas in 1 case dicentric isoderivative chromosome 22 was detected in amount of 1-5 copies per metaphase plate (Fig. 1). Presence of two copies of BCR-ABL on both arms of isoderivative 22 in all cases was confirmed by FISH on metaphase plates. It was hence proved that the detected isoderivative 22 in these 4 patients was composed of the long arms of Ph-chromosome with fragments of chromosome 22 and 9 linked by centromere of chromosome 22. Presence of two copies of BCR-ABL was also confirmed by FISH for the patient with dicentric isoderivative chromosome 22. However, in this case the isoderivative comprised two cetromeres of chromosome 22 and the long arms were connected by telomeric areas of the translocated fragments of chromosome 9. Total number of BCR-ABL copies in cells with isoderivative was 2-10.The described abnormalities were detected in 4 patients treated with imatinib. Therapy was subsequently changed to nilotinib in 3 of them and to dasatinib in 1 patient. After switching to nilotinib cytogenetic response was not achieved in 2 patients who subsequently died of disease progression. In case of dasatinib the patient also failed to reach cytogenetic response. Only in one patient after 2 years of nilotinib complete cytogenetic response (CCyR) was obtained. In remaining 5th patient who failed after 1 year of imatinib without any clonal evolution treatment was changed to nilotinib. After 6 months of this treatment CCyR was achieved, however after 12 months occurrence of isoderivative 22 was for the first time detected in 50% of the cells. The patient currently continues being followed.
Conclusion
The paper describes 5 cases of rare structural modifications of derivative chromosome 22, leading to increased numbers of copies of BCR-ABL gene. In majority of these cases patients were resistant to treatment with tyrosine kinase inhibitors. Detected aberrations most probably represent one of the mechanisms of the secondary resistance and disease progression in CML.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Cytogenetic abnormalities, Ph chromosome
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