NOVEL DYNAMIN2 MUTATION IN ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Ge Z. 06/09/16; 132421; E872
Prof. Zheng Ge
Contributions
Contributions
Abstract
Abstract: E872
Type: Eposter Presentation
Background
Dynamin 2 (DNM2), a GTPase is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. Recently DNM2 genetic mutations are identified in a subtype of T-cell acute lymphoblastic leukaemia (T-ALL) termed “early T-cell precursor” (ETP) ALL that comprises up to 15% of T-ALL, and is associated with treatment failure. However, study on DNM2 genetic mutations in adult ALL is rare.
Aims
To characterize the novel DNM2 mutations in Chinese adult T-ALL patients.
Methods
Bone marrow (BM) samples from 42 newly diagnosed T-ALL patients [31 male with median age 26 (16-62), 11 female with median age 29 (19-60)] were collected between July 2010 and December 2014 at the First Affiliated Hospital of Nanjing Medical University. The diagnosis of ALL was made according to the morphologic, immunophenotypic, cytogenetic and molecular criteria of WHO Diagnosis and Classification of ALL (2008). All the patients provided their written informed consent in accordance with the Declaration of Helsinki before enrollment in the study. The study was approved by the Institutional Review Board of the Nanjing Medical University. We performed mutational analyses of DNM2 exons 2-22. Exons in NOTCH1, FBXW7, PHF6, PTEN, JAK1 and IL-7R were also screened. Conventional cytogenetic analysis was performed at the time of diagnosis, using unstimulated short-term cultures according to the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN). For each sample, at least 20 BM metaphase cells were analyzed. Immunophenotypic analyses were performed by flow cytometry on fresh BM samples. The cell-surface antigen was defined positive when fluorescence intensity of at least 20% of cells exceeded fluorescence of negative control.
Results
DNM2 mutations were identified in 4 of 42 T-ALL patients (9.5%). All the four cases were point mutations (c.1081C>T, c.1453T>C, c.1609G>A and c. 1801C>T), which is located in exon 8, 13, 16 and 18. In the four identified mutations, one is nonsense mutation and three are missense mutations. All of the four mutations were lead to amino acid changes (R361X, Y485H, G537S and R601W). The R361X and Y485H are located in middle(MID) domain, while G537S and R601W in pleckstrin homology(PH) domain of DNM2. Interestingly, we found that the four patients with DNM2 mutations co-existed with NOTCH1 mutations, 3 of the 4 cases co-existed with two NOTCH1 mutations (point mutations and / or indel mutations), which were located in NOTCH1 exon 26, 27 and 34. Moreover, 3 of the 4 patients with DNM2 mutations were also concomitant with PHF6 mutations which were located in PHF6 exon 4, 5 and 8. The clinical characteristics of the patients with DNM2 mutations were further analyzed. It showed that one patient relapsed, one patient had initial high WBC, and two patients had complex karyotype. Importantly, the days for reaching the complete remission after induction chemotherapy were over 4 weeks for all these patients. These data indicated that the patients with DNM2 mutations in this cohort of adult T-ALL had poor prognosis.
Conclusion
We identified 4 novel DNM2 mutations and the co-existence of mutations in NOTCH1/PHF6 in adult T-ALL patients. We also observed the association of DNM2 mutations with poor prognosis. Our finding suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
Session topic: E-poster
Keyword(s): Adult, Leukemia, Mutation, T cell
Type: Eposter Presentation
Background
Dynamin 2 (DNM2), a GTPase is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. Recently DNM2 genetic mutations are identified in a subtype of T-cell acute lymphoblastic leukaemia (T-ALL) termed “early T-cell precursor” (ETP) ALL that comprises up to 15% of T-ALL, and is associated with treatment failure. However, study on DNM2 genetic mutations in adult ALL is rare.
Aims
To characterize the novel DNM2 mutations in Chinese adult T-ALL patients.
Methods
Bone marrow (BM) samples from 42 newly diagnosed T-ALL patients [31 male with median age 26 (16-62), 11 female with median age 29 (19-60)] were collected between July 2010 and December 2014 at the First Affiliated Hospital of Nanjing Medical University. The diagnosis of ALL was made according to the morphologic, immunophenotypic, cytogenetic and molecular criteria of WHO Diagnosis and Classification of ALL (2008). All the patients provided their written informed consent in accordance with the Declaration of Helsinki before enrollment in the study. The study was approved by the Institutional Review Board of the Nanjing Medical University. We performed mutational analyses of DNM2 exons 2-22. Exons in NOTCH1, FBXW7, PHF6, PTEN, JAK1 and IL-7R were also screened. Conventional cytogenetic analysis was performed at the time of diagnosis, using unstimulated short-term cultures according to the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN). For each sample, at least 20 BM metaphase cells were analyzed. Immunophenotypic analyses were performed by flow cytometry on fresh BM samples. The cell-surface antigen was defined positive when fluorescence intensity of at least 20% of cells exceeded fluorescence of negative control.
Results
DNM2 mutations were identified in 4 of 42 T-ALL patients (9.5%). All the four cases were point mutations (c.1081C>T, c.1453T>C, c.1609G>A and c. 1801C>T), which is located in exon 8, 13, 16 and 18. In the four identified mutations, one is nonsense mutation and three are missense mutations. All of the four mutations were lead to amino acid changes (R361X, Y485H, G537S and R601W). The R361X and Y485H are located in middle(MID) domain, while G537S and R601W in pleckstrin homology(PH) domain of DNM2. Interestingly, we found that the four patients with DNM2 mutations co-existed with NOTCH1 mutations, 3 of the 4 cases co-existed with two NOTCH1 mutations (point mutations and / or indel mutations), which were located in NOTCH1 exon 26, 27 and 34. Moreover, 3 of the 4 patients with DNM2 mutations were also concomitant with PHF6 mutations which were located in PHF6 exon 4, 5 and 8. The clinical characteristics of the patients with DNM2 mutations were further analyzed. It showed that one patient relapsed, one patient had initial high WBC, and two patients had complex karyotype. Importantly, the days for reaching the complete remission after induction chemotherapy were over 4 weeks for all these patients. These data indicated that the patients with DNM2 mutations in this cohort of adult T-ALL had poor prognosis.
Conclusion
We identified 4 novel DNM2 mutations and the co-existence of mutations in NOTCH1/PHF6 in adult T-ALL patients. We also observed the association of DNM2 mutations with poor prognosis. Our finding suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
Session topic: E-poster
Keyword(s): Adult, Leukemia, Mutation, T cell
Abstract: E872
Type: Eposter Presentation
Background
Dynamin 2 (DNM2), a GTPase is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. Recently DNM2 genetic mutations are identified in a subtype of T-cell acute lymphoblastic leukaemia (T-ALL) termed “early T-cell precursor” (ETP) ALL that comprises up to 15% of T-ALL, and is associated with treatment failure. However, study on DNM2 genetic mutations in adult ALL is rare.
Aims
To characterize the novel DNM2 mutations in Chinese adult T-ALL patients.
Methods
Bone marrow (BM) samples from 42 newly diagnosed T-ALL patients [31 male with median age 26 (16-62), 11 female with median age 29 (19-60)] were collected between July 2010 and December 2014 at the First Affiliated Hospital of Nanjing Medical University. The diagnosis of ALL was made according to the morphologic, immunophenotypic, cytogenetic and molecular criteria of WHO Diagnosis and Classification of ALL (2008). All the patients provided their written informed consent in accordance with the Declaration of Helsinki before enrollment in the study. The study was approved by the Institutional Review Board of the Nanjing Medical University. We performed mutational analyses of DNM2 exons 2-22. Exons in NOTCH1, FBXW7, PHF6, PTEN, JAK1 and IL-7R were also screened. Conventional cytogenetic analysis was performed at the time of diagnosis, using unstimulated short-term cultures according to the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN). For each sample, at least 20 BM metaphase cells were analyzed. Immunophenotypic analyses were performed by flow cytometry on fresh BM samples. The cell-surface antigen was defined positive when fluorescence intensity of at least 20% of cells exceeded fluorescence of negative control.
Results
DNM2 mutations were identified in 4 of 42 T-ALL patients (9.5%). All the four cases were point mutations (c.1081C>T, c.1453T>C, c.1609G>A and c. 1801C>T), which is located in exon 8, 13, 16 and 18. In the four identified mutations, one is nonsense mutation and three are missense mutations. All of the four mutations were lead to amino acid changes (R361X, Y485H, G537S and R601W). The R361X and Y485H are located in middle(MID) domain, while G537S and R601W in pleckstrin homology(PH) domain of DNM2. Interestingly, we found that the four patients with DNM2 mutations co-existed with NOTCH1 mutations, 3 of the 4 cases co-existed with two NOTCH1 mutations (point mutations and / or indel mutations), which were located in NOTCH1 exon 26, 27 and 34. Moreover, 3 of the 4 patients with DNM2 mutations were also concomitant with PHF6 mutations which were located in PHF6 exon 4, 5 and 8. The clinical characteristics of the patients with DNM2 mutations were further analyzed. It showed that one patient relapsed, one patient had initial high WBC, and two patients had complex karyotype. Importantly, the days for reaching the complete remission after induction chemotherapy were over 4 weeks for all these patients. These data indicated that the patients with DNM2 mutations in this cohort of adult T-ALL had poor prognosis.
Conclusion
We identified 4 novel DNM2 mutations and the co-existence of mutations in NOTCH1/PHF6 in adult T-ALL patients. We also observed the association of DNM2 mutations with poor prognosis. Our finding suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
Session topic: E-poster
Keyword(s): Adult, Leukemia, Mutation, T cell
Type: Eposter Presentation
Background
Dynamin 2 (DNM2), a GTPase is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. Recently DNM2 genetic mutations are identified in a subtype of T-cell acute lymphoblastic leukaemia (T-ALL) termed “early T-cell precursor” (ETP) ALL that comprises up to 15% of T-ALL, and is associated with treatment failure. However, study on DNM2 genetic mutations in adult ALL is rare.
Aims
To characterize the novel DNM2 mutations in Chinese adult T-ALL patients.
Methods
Bone marrow (BM) samples from 42 newly diagnosed T-ALL patients [31 male with median age 26 (16-62), 11 female with median age 29 (19-60)] were collected between July 2010 and December 2014 at the First Affiliated Hospital of Nanjing Medical University. The diagnosis of ALL was made according to the morphologic, immunophenotypic, cytogenetic and molecular criteria of WHO Diagnosis and Classification of ALL (2008). All the patients provided their written informed consent in accordance with the Declaration of Helsinki before enrollment in the study. The study was approved by the Institutional Review Board of the Nanjing Medical University. We performed mutational analyses of DNM2 exons 2-22. Exons in NOTCH1, FBXW7, PHF6, PTEN, JAK1 and IL-7R were also screened. Conventional cytogenetic analysis was performed at the time of diagnosis, using unstimulated short-term cultures according to the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN). For each sample, at least 20 BM metaphase cells were analyzed. Immunophenotypic analyses were performed by flow cytometry on fresh BM samples. The cell-surface antigen was defined positive when fluorescence intensity of at least 20% of cells exceeded fluorescence of negative control.
Results
DNM2 mutations were identified in 4 of 42 T-ALL patients (9.5%). All the four cases were point mutations (c.1081C>T, c.1453T>C, c.1609G>A and c. 1801C>T), which is located in exon 8, 13, 16 and 18. In the four identified mutations, one is nonsense mutation and three are missense mutations. All of the four mutations were lead to amino acid changes (R361X, Y485H, G537S and R601W). The R361X and Y485H are located in middle(MID) domain, while G537S and R601W in pleckstrin homology(PH) domain of DNM2. Interestingly, we found that the four patients with DNM2 mutations co-existed with NOTCH1 mutations, 3 of the 4 cases co-existed with two NOTCH1 mutations (point mutations and / or indel mutations), which were located in NOTCH1 exon 26, 27 and 34. Moreover, 3 of the 4 patients with DNM2 mutations were also concomitant with PHF6 mutations which were located in PHF6 exon 4, 5 and 8. The clinical characteristics of the patients with DNM2 mutations were further analyzed. It showed that one patient relapsed, one patient had initial high WBC, and two patients had complex karyotype. Importantly, the days for reaching the complete remission after induction chemotherapy were over 4 weeks for all these patients. These data indicated that the patients with DNM2 mutations in this cohort of adult T-ALL had poor prognosis.
Conclusion
We identified 4 novel DNM2 mutations and the co-existence of mutations in NOTCH1/PHF6 in adult T-ALL patients. We also observed the association of DNM2 mutations with poor prognosis. Our finding suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
Session topic: E-poster
Keyword(s): Adult, Leukemia, Mutation, T cell
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