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NEW POTENTIAL CANDIDATE GENES IN MANTLE CELL LYMPHOMA
Author(s): ,
Oriane Cédile
Affiliations:
Haematology-Pathology Research Laboratory,Odense University Hospital,Odense C,Denmark;Department of Haematology,Odense University Hospital,Odense C,Denmark
,
Marcus Celik Hansen
Affiliations:
Haematology-Pathology Research Laboratory,Odense University Hospital,Odense C,Denmark;Department of Haematology,Odense University Hospital,Odense C,Denmark
,
Lene Hyldahl Ebbesen
Affiliations:
Department of Haematology,Aarhus University Hospital,Aarhus,Denmark
,
Hans Herluf Nørgaard Bentzen
Affiliations:
Department of Haematology,Aarhus University Hospital,Aarhus,Denmark
,
Mads Thomassen
Affiliations:
Department of Clinical Genetics,Odense University Hospital,Odense C,Denmark
,
Torben A Kruse
Affiliations:
Department of Clinical Genetics,Odense University Hospital,Odense C,Denmark
,
Stephanie Kavan
Affiliations:
Department of Clinical Genetics,Odense University Hospital,Odense C,Denmark
,
Michael Boe Møller
Affiliations:
Haematology-Pathology Research Laboratory,Odense University Hospital,Odense C,Denmark;Department of Pathology,Odense University Hospital,Odense C,Denmark
,
Thomas Kielsgaard Kristensen
Affiliations:
Haematology-Pathology Research Laboratory,Odense University Hospital,Odense C,Denmark;Department of Pathology,Odense University Hospital,Odense C,Denmark
,
Jacob Haaber
Affiliations:
Department of Haematology,Odense University Hospital,Odense C,Denmark
,
Niels Abildgaard
Affiliations:
Department of Haematology,Odense University Hospital,Odense C,Denmark
Charlotte Guldborg Nyvold
Affiliations:
Haematology-Pathology Research Laboratory,Odense University Hospital,Odense C,Denmark;Department of Haematology,Odense University Hospital,Odense C,Denmark
(Abstract release date: 05/17/18) EHA Library. Cédile O. 06/14/18; 216600; PB2322
Oriane Cédile
Oriane Cédile
Contributions
Abstract

Abstract: PB2322

Type: Publication Only

Background

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma characterized by the translocation of the cell cycle regulator cyclin D1 (CCND1) under control of the immunoglobulin heavy chain (IGH) locus leading to the constitutive overexpression of CCND1 and cell cycle deregulation. The survival of MCL patients is still poor, especially for patients resistant to frontline therapy. Despite the remissions observed in patients, relapses often occur with disseminated lymphoma and are often more difficult to treat. There is a need for a better understanding of the clonal heterogeneity in MCL and to identify new genes, which could be targeted by novel drugs or be used as biomarkers to predict response to treatment.

Aims

We previously showed the genetic complexity and clonal evolution in MCL by exome analysis in paired samples at diagnosis and relapse and identified new mutations in genes involved in B-cell signaling pathways. In the current study, we have investigated the heterogeneity in gene expression in the same cohort of patients.

Methods

Malignant B cells at diagnosis and relapse from 4 MCL patients were sorted as presented at the EHA meeting in 2017 and subjected to total RNA sequencing together with CD19+ enriched B cells from 3 healthy donors. Six genes aberrantly expressed in MCL samples compared to healthy CD19+ B cells were selected and validated by qPCR in independent cohorts of diagnostic samples from MCL and chronic lymphocytic leukemia (CLL) patients. Peripheral blood mononuclear cells from 20 MCL and 20 CLL patients as well as CD19+ enriched B cells from 10 healthy donors were included. Exemption from informed consent was approved by the National Ethical Committee.

Results

The transcriptome analysis pointed to 19 upregulated genes. The expression of these genes varied between patients but also between paired diagnosis and relapse samples. This suggested clonal evolution or malignant progression and inter-patient heterogeneity, supporting our previous study. We selected 6 upregulated genes that were mainly associated to B cell signaling (CD1c, BLNK, MAP4K1, CCDC50, LILRA4 and PTPRJ) and explored the expression levels in MCL, CLL and healthy CD19+ B cells. While BLNK and CCDC50 were previously reported as highly expressed in MCL, we showed that BLNK expression was similar in MCL and CLL but slightly decreased compared to healthy CD19+ B cells. No difference was observed between MCL, CLL and healthy CD19+ B cells for the CCDC50 or MAP4K1 genes. CD1c was detected in MCL and CLL, although downregulated compared to healthy CD19+ B cells, with a lower expression in CLL than in MCL. This supports its expression in malignant B cells. Few studies detected PTPRJ and LILRA4 in MCL. We showed that PTPRJ was upregulated in MCL and CLL compared to healthy CD19+ B cells with a higher expression in MCL than in CLL. Interestingly, both MCL and CLL displayed 2 clear and different LILRA4 expression levels where the expression in healthy CD19+ B cells displayed an intermediate level.

Conclusion

Our transcriptome analysis supports the genetic complexity and the clonal evolution in MCL. It also identifies the genes CD1c, PTPRJ and LILRA4 to be aberrantly expressed in MCL with differential regulation of CD1c and PTPRJ in MCL and CLL. This study proposes new candidate genes to target with drugs or to use as biomarkers in MCL.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): Quantitative RT-PCR, Transcriptional regulation, Mantle cell lymphoma, Molecular markers

Abstract: PB2322

Type: Publication Only

Background

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma characterized by the translocation of the cell cycle regulator cyclin D1 (CCND1) under control of the immunoglobulin heavy chain (IGH) locus leading to the constitutive overexpression of CCND1 and cell cycle deregulation. The survival of MCL patients is still poor, especially for patients resistant to frontline therapy. Despite the remissions observed in patients, relapses often occur with disseminated lymphoma and are often more difficult to treat. There is a need for a better understanding of the clonal heterogeneity in MCL and to identify new genes, which could be targeted by novel drugs or be used as biomarkers to predict response to treatment.

Aims

We previously showed the genetic complexity and clonal evolution in MCL by exome analysis in paired samples at diagnosis and relapse and identified new mutations in genes involved in B-cell signaling pathways. In the current study, we have investigated the heterogeneity in gene expression in the same cohort of patients.

Methods

Malignant B cells at diagnosis and relapse from 4 MCL patients were sorted as presented at the EHA meeting in 2017 and subjected to total RNA sequencing together with CD19+ enriched B cells from 3 healthy donors. Six genes aberrantly expressed in MCL samples compared to healthy CD19+ B cells were selected and validated by qPCR in independent cohorts of diagnostic samples from MCL and chronic lymphocytic leukemia (CLL) patients. Peripheral blood mononuclear cells from 20 MCL and 20 CLL patients as well as CD19+ enriched B cells from 10 healthy donors were included. Exemption from informed consent was approved by the National Ethical Committee.

Results

The transcriptome analysis pointed to 19 upregulated genes. The expression of these genes varied between patients but also between paired diagnosis and relapse samples. This suggested clonal evolution or malignant progression and inter-patient heterogeneity, supporting our previous study. We selected 6 upregulated genes that were mainly associated to B cell signaling (CD1c, BLNK, MAP4K1, CCDC50, LILRA4 and PTPRJ) and explored the expression levels in MCL, CLL and healthy CD19+ B cells. While BLNK and CCDC50 were previously reported as highly expressed in MCL, we showed that BLNK expression was similar in MCL and CLL but slightly decreased compared to healthy CD19+ B cells. No difference was observed between MCL, CLL and healthy CD19+ B cells for the CCDC50 or MAP4K1 genes. CD1c was detected in MCL and CLL, although downregulated compared to healthy CD19+ B cells, with a lower expression in CLL than in MCL. This supports its expression in malignant B cells. Few studies detected PTPRJ and LILRA4 in MCL. We showed that PTPRJ was upregulated in MCL and CLL compared to healthy CD19+ B cells with a higher expression in MCL than in CLL. Interestingly, both MCL and CLL displayed 2 clear and different LILRA4 expression levels where the expression in healthy CD19+ B cells displayed an intermediate level.

Conclusion

Our transcriptome analysis supports the genetic complexity and the clonal evolution in MCL. It also identifies the genes CD1c, PTPRJ and LILRA4 to be aberrantly expressed in MCL with differential regulation of CD1c and PTPRJ in MCL and CLL. This study proposes new candidate genes to target with drugs or to use as biomarkers in MCL.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): Quantitative RT-PCR, Transcriptional regulation, Mantle cell lymphoma, Molecular markers

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