MEF2C DYSREGULATION IS ASSOCIATED WITH CDKN1B DELETIONS AND PREDICTS POOR GLUCOCORTICOID RESPONSE IN PEDIATRIC T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Colomer-Lahiguera S. 06/10/16; 133139; P151
Dr. Sara Colomer-Lahiguera
Contributions
Contributions
Abstract
Abstract: P151
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors resulting from the malignant transformation of T-cell progenitors and account for 10‑15% of pediatric ALL cases. T-ALL is a heterogeneous disease characterized by a number of specific genetic alterations, which define molecular subgroups associated with distinct gene expression signatures, including the TAL/LMO, TLX1, TLX3, HOXA clusters as well as the recently identified proliferative and immature subtypes, typically overexpressing NKX2‑1 or NKX2‑2 and MEF2C, respectively. The latter, at least in part, overlaps with early T-cell phenotype- (ETP-) like ALL. However, a number of recurrent abnormalities such as CDKN1B deletions occurring in about 12% of T-ALL have not as yet been assigned to any specific disease entity.
Aims
In this study we sought to characterize pediatric T-ALL patients with CDKN1B deletions, which represent one of the most frequent copy number alterations, in more detail.
Methods
Array comparative genomic hybridization (aCGH) of 102 pediatric T-ALL patients enrolled in the Austrian ALL-BFM 90, 95 or 2000 clinical trials was performed. Cytogenetic analysis and immunophenotyping were done as part of the routine diagnostic work-up. The presence of specific chromosomal abnormalities was furthermore determined by fluorescence in situ hybridization (FISH) and/or RT-PCR. Moreover, the samples were subjected to RT-qPCR for MEF2C expression.
Results
By aCGH analysis and quantitative genomic PCR we detected the presence of CDKN1B deletions in 14 cases. Further genetic characterization of these cases led to their classification into the major T-ALL subtypes: TAL/LMO (n=1), TLX1 (n=1),TLX3 (n=1), or HOXA (n=3). Since many of the cases did not fall into any of these groups, we determined whether they belonged to the immature cluster characterized by MEF2C expression and compared them to CDKN1B wild-type cases. Remarkably, while only 14% (4/28) of CDKN1B wild-type samples showed MEF2C dysregulation, this was observed in 54% (6/11) of the CDKN1B-deleted cases for which appropriate material for RT-qPCR was available (p=0.017), suggesting an association between loss of CDKN1B and MEF2C expression. Since MEF2C is considered as one of the driving oncogenes of immature/ETP-like ALL, we next evaluated whether the MEF2C-dysregulated cases displayed the immunophenotypic characteristics of ETP-ALL: CD1a/CD4/CD8 negative; absent or weak CD5, and expression of one or more myeloid and/or stem cell antigens. Notably, while all cases immunophenotypically defined as ETP-like cases showed upregulation of MEF2C expression, only 30% (3/10) of MEF2C-dysregulated cases showed an ETP-like phenotype. However, virtually all of them expressed myeloid or B-lineage-specific markers, suggesting a certain lineage plasticity. Furthermore, high MEF2C expression levels in primary leukemia samples were associated with a significantly higher proportion of the patients being resistant to glucocorticoid therapy (p=0.0033).
Conclusion
In summary, our data provide evidence that CDKN1B deletions are associated with immature/MEF2C-dysregulated T-ALL and that MEF2C overexpression, though associated with, is not exclusively found in ETP-like ALL. Furthermore, our results indicate that MEF2C expression is associated with or may even be predictive of the response to glucocorticoid treatment.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Immunophenotype, P27Kip1, T cell acute lymphoblastic leukemia
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors resulting from the malignant transformation of T-cell progenitors and account for 10‑15% of pediatric ALL cases. T-ALL is a heterogeneous disease characterized by a number of specific genetic alterations, which define molecular subgroups associated with distinct gene expression signatures, including the TAL/LMO, TLX1, TLX3, HOXA clusters as well as the recently identified proliferative and immature subtypes, typically overexpressing NKX2‑1 or NKX2‑2 and MEF2C, respectively. The latter, at least in part, overlaps with early T-cell phenotype- (ETP-) like ALL. However, a number of recurrent abnormalities such as CDKN1B deletions occurring in about 12% of T-ALL have not as yet been assigned to any specific disease entity.
Aims
In this study we sought to characterize pediatric T-ALL patients with CDKN1B deletions, which represent one of the most frequent copy number alterations, in more detail.
Methods
Array comparative genomic hybridization (aCGH) of 102 pediatric T-ALL patients enrolled in the Austrian ALL-BFM 90, 95 or 2000 clinical trials was performed. Cytogenetic analysis and immunophenotyping were done as part of the routine diagnostic work-up. The presence of specific chromosomal abnormalities was furthermore determined by fluorescence in situ hybridization (FISH) and/or RT-PCR. Moreover, the samples were subjected to RT-qPCR for MEF2C expression.
Results
By aCGH analysis and quantitative genomic PCR we detected the presence of CDKN1B deletions in 14 cases. Further genetic characterization of these cases led to their classification into the major T-ALL subtypes: TAL/LMO (n=1), TLX1 (n=1),TLX3 (n=1), or HOXA (n=3). Since many of the cases did not fall into any of these groups, we determined whether they belonged to the immature cluster characterized by MEF2C expression and compared them to CDKN1B wild-type cases. Remarkably, while only 14% (4/28) of CDKN1B wild-type samples showed MEF2C dysregulation, this was observed in 54% (6/11) of the CDKN1B-deleted cases for which appropriate material for RT-qPCR was available (p=0.017), suggesting an association between loss of CDKN1B and MEF2C expression. Since MEF2C is considered as one of the driving oncogenes of immature/ETP-like ALL, we next evaluated whether the MEF2C-dysregulated cases displayed the immunophenotypic characteristics of ETP-ALL: CD1a/CD4/CD8 negative; absent or weak CD5, and expression of one or more myeloid and/or stem cell antigens. Notably, while all cases immunophenotypically defined as ETP-like cases showed upregulation of MEF2C expression, only 30% (3/10) of MEF2C-dysregulated cases showed an ETP-like phenotype. However, virtually all of them expressed myeloid or B-lineage-specific markers, suggesting a certain lineage plasticity. Furthermore, high MEF2C expression levels in primary leukemia samples were associated with a significantly higher proportion of the patients being resistant to glucocorticoid therapy (p=0.0033).
Conclusion
In summary, our data provide evidence that CDKN1B deletions are associated with immature/MEF2C-dysregulated T-ALL and that MEF2C overexpression, though associated with, is not exclusively found in ETP-like ALL. Furthermore, our results indicate that MEF2C expression is associated with or may even be predictive of the response to glucocorticoid treatment.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Immunophenotype, P27Kip1, T cell acute lymphoblastic leukemia
Abstract: P151
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors resulting from the malignant transformation of T-cell progenitors and account for 10‑15% of pediatric ALL cases. T-ALL is a heterogeneous disease characterized by a number of specific genetic alterations, which define molecular subgroups associated with distinct gene expression signatures, including the TAL/LMO, TLX1, TLX3, HOXA clusters as well as the recently identified proliferative and immature subtypes, typically overexpressing NKX2‑1 or NKX2‑2 and MEF2C, respectively. The latter, at least in part, overlaps with early T-cell phenotype- (ETP-) like ALL. However, a number of recurrent abnormalities such as CDKN1B deletions occurring in about 12% of T-ALL have not as yet been assigned to any specific disease entity.
Aims
In this study we sought to characterize pediatric T-ALL patients with CDKN1B deletions, which represent one of the most frequent copy number alterations, in more detail.
Methods
Array comparative genomic hybridization (aCGH) of 102 pediatric T-ALL patients enrolled in the Austrian ALL-BFM 90, 95 or 2000 clinical trials was performed. Cytogenetic analysis and immunophenotyping were done as part of the routine diagnostic work-up. The presence of specific chromosomal abnormalities was furthermore determined by fluorescence in situ hybridization (FISH) and/or RT-PCR. Moreover, the samples were subjected to RT-qPCR for MEF2C expression.
Results
By aCGH analysis and quantitative genomic PCR we detected the presence of CDKN1B deletions in 14 cases. Further genetic characterization of these cases led to their classification into the major T-ALL subtypes: TAL/LMO (n=1), TLX1 (n=1),TLX3 (n=1), or HOXA (n=3). Since many of the cases did not fall into any of these groups, we determined whether they belonged to the immature cluster characterized by MEF2C expression and compared them to CDKN1B wild-type cases. Remarkably, while only 14% (4/28) of CDKN1B wild-type samples showed MEF2C dysregulation, this was observed in 54% (6/11) of the CDKN1B-deleted cases for which appropriate material for RT-qPCR was available (p=0.017), suggesting an association between loss of CDKN1B and MEF2C expression. Since MEF2C is considered as one of the driving oncogenes of immature/ETP-like ALL, we next evaluated whether the MEF2C-dysregulated cases displayed the immunophenotypic characteristics of ETP-ALL: CD1a/CD4/CD8 negative; absent or weak CD5, and expression of one or more myeloid and/or stem cell antigens. Notably, while all cases immunophenotypically defined as ETP-like cases showed upregulation of MEF2C expression, only 30% (3/10) of MEF2C-dysregulated cases showed an ETP-like phenotype. However, virtually all of them expressed myeloid or B-lineage-specific markers, suggesting a certain lineage plasticity. Furthermore, high MEF2C expression levels in primary leukemia samples were associated with a significantly higher proportion of the patients being resistant to glucocorticoid therapy (p=0.0033).
Conclusion
In summary, our data provide evidence that CDKN1B deletions are associated with immature/MEF2C-dysregulated T-ALL and that MEF2C overexpression, though associated with, is not exclusively found in ETP-like ALL. Furthermore, our results indicate that MEF2C expression is associated with or may even be predictive of the response to glucocorticoid treatment.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Immunophenotype, P27Kip1, T cell acute lymphoblastic leukemia
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors resulting from the malignant transformation of T-cell progenitors and account for 10‑15% of pediatric ALL cases. T-ALL is a heterogeneous disease characterized by a number of specific genetic alterations, which define molecular subgroups associated with distinct gene expression signatures, including the TAL/LMO, TLX1, TLX3, HOXA clusters as well as the recently identified proliferative and immature subtypes, typically overexpressing NKX2‑1 or NKX2‑2 and MEF2C, respectively. The latter, at least in part, overlaps with early T-cell phenotype- (ETP-) like ALL. However, a number of recurrent abnormalities such as CDKN1B deletions occurring in about 12% of T-ALL have not as yet been assigned to any specific disease entity.
Aims
In this study we sought to characterize pediatric T-ALL patients with CDKN1B deletions, which represent one of the most frequent copy number alterations, in more detail.
Methods
Array comparative genomic hybridization (aCGH) of 102 pediatric T-ALL patients enrolled in the Austrian ALL-BFM 90, 95 or 2000 clinical trials was performed. Cytogenetic analysis and immunophenotyping were done as part of the routine diagnostic work-up. The presence of specific chromosomal abnormalities was furthermore determined by fluorescence in situ hybridization (FISH) and/or RT-PCR. Moreover, the samples were subjected to RT-qPCR for MEF2C expression.
Results
By aCGH analysis and quantitative genomic PCR we detected the presence of CDKN1B deletions in 14 cases. Further genetic characterization of these cases led to their classification into the major T-ALL subtypes: TAL/LMO (n=1), TLX1 (n=1),TLX3 (n=1), or HOXA (n=3). Since many of the cases did not fall into any of these groups, we determined whether they belonged to the immature cluster characterized by MEF2C expression and compared them to CDKN1B wild-type cases. Remarkably, while only 14% (4/28) of CDKN1B wild-type samples showed MEF2C dysregulation, this was observed in 54% (6/11) of the CDKN1B-deleted cases for which appropriate material for RT-qPCR was available (p=0.017), suggesting an association between loss of CDKN1B and MEF2C expression. Since MEF2C is considered as one of the driving oncogenes of immature/ETP-like ALL, we next evaluated whether the MEF2C-dysregulated cases displayed the immunophenotypic characteristics of ETP-ALL: CD1a/CD4/CD8 negative; absent or weak CD5, and expression of one or more myeloid and/or stem cell antigens. Notably, while all cases immunophenotypically defined as ETP-like cases showed upregulation of MEF2C expression, only 30% (3/10) of MEF2C-dysregulated cases showed an ETP-like phenotype. However, virtually all of them expressed myeloid or B-lineage-specific markers, suggesting a certain lineage plasticity. Furthermore, high MEF2C expression levels in primary leukemia samples were associated with a significantly higher proportion of the patients being resistant to glucocorticoid therapy (p=0.0033).
Conclusion
In summary, our data provide evidence that CDKN1B deletions are associated with immature/MEF2C-dysregulated T-ALL and that MEF2C overexpression, though associated with, is not exclusively found in ETP-like ALL. Furthermore, our results indicate that MEF2C expression is associated with or may even be predictive of the response to glucocorticoid treatment.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Immunophenotype, P27Kip1, T cell acute lymphoblastic leukemia
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