Analysis of Myc Aberrations in Mantle Cell Lymphoma and Drug Target Identification
(2021) KIMM05 20211Department of Immunotechnology
- Abstract
- Mantle cell lymphoma (MCL) with Myc aberrations has previously been shown to be associated with poor survival and worse response to current treatment strategies. This study aims to investigate the association between Myc overexpression and clinical outcome and to identify drugs targeting MCL with Myc alterations. Data from the two patient cohorts BLISS and N-MCL2/3 was analyzed, and the association between Myc status and patient characteristics was evaluated. Results from a drug screening on six MCL cell lines were analyzed with respect to how the drugs targeted the cell lines with Myc and/or p53/TP53 aberrations. Our data confirmed that Myc overexpression is indeed associated with worse prognosis. We also identified a subgroup of patients... (More)
- Mantle cell lymphoma (MCL) with Myc aberrations has previously been shown to be associated with poor survival and worse response to current treatment strategies. This study aims to investigate the association between Myc overexpression and clinical outcome and to identify drugs targeting MCL with Myc alterations. Data from the two patient cohorts BLISS and N-MCL2/3 was analyzed, and the association between Myc status and patient characteristics was evaluated. Results from a drug screening on six MCL cell lines were analyzed with respect to how the drugs targeted the cell lines with Myc and/or p53/TP53 aberrations. Our data confirmed that Myc overexpression is indeed associated with worse prognosis. We also identified a subgroup of patients with tumors that both overexpressed Myc and had p53/TP53 aberrations that was associated with a survival even worse than patients with tumors overexpressing Myc or having p53/TP53 aberrations alone. In addition to p53/TP53 aberrations, Myc overexpression was significantly correlated to non-classic morphology, high Ki67 expression, age, and reduced expression of CD8 positive cells. The two kinases PLK1 and Wee1 induced cell death in both the cell lines with Myc overexpression and the cell lines with p53/TP53 mutations. They also reduced cell proliferation in the cell lines overexpressing Myc. Therefore, PLK1 and Wee1 are considered possible drug target candidates in MCL with Myc aberrations. (Less)
- Popular Abstract
- Cancer is the second leading cause of death globally and there is a constant increase in cancer incidence. However, the death rates are decreasing, which partly can be explained by advances in treatments. To obtain a continued reduction of death rates, it is of great importance to further improve the treatments for cancer patients.
Cancer is an umbrella term for many different diseases that are characterized by uncontrolled cell division. The focus of this master thesis is mantle cell lymphoma. Mantle cell lymphoma is an aggressive and rare type of cancer that arises in the white blood cells. The treatments of the disease have significantly improved over the past years, which has increased survival for most patients. Although, there... (More) - Cancer is the second leading cause of death globally and there is a constant increase in cancer incidence. However, the death rates are decreasing, which partly can be explained by advances in treatments. To obtain a continued reduction of death rates, it is of great importance to further improve the treatments for cancer patients.
Cancer is an umbrella term for many different diseases that are characterized by uncontrolled cell division. The focus of this master thesis is mantle cell lymphoma. Mantle cell lymphoma is an aggressive and rare type of cancer that arises in the white blood cells. The treatments of the disease have significantly improved over the past years, which has increased survival for most patients. Although, there are still some patients that do not respond to these new treatment strategies and therefore subgroups of patients have a very poor survival.
A specific protein that has previously been associated to poor response to current treatment strategies and short survival in mantle cell lymphoma is Myc. An elevated amount of this protein can create unbalance in the cell and results in increased cell growth. We had access to clinical data from 229 mantle cell lymphoma patients and investigated if there was a correlation between a high amount of the protein Myc and a poor survival in these patients. We found that Myc was indeed associated with an increased risk of dying.
After identifying this group of patients with poor survival, we aimed to find new treatments for these patients. Mantle cell lymphoma cells that continuously are kept viable in cell cultures were used to study the expression of Myc. Data was available from a previous study, in which the effect of 176 drugs had been evaluated. Two drugs that showed high capability to promote cell death in mantle cell lymphoma regardless of the abundance of Myc were identified. These two drugs target the proteins PLK1 and Wee1, respectively. The primary samples from the 229 mantle cell lymphoma patients were used to explore the correlation between PLK1, Wee1 and Myc protein levels. We found that a high amount of Myc was correlated to a high amount of PLK1 and Wee1 in the patients.
In conclusion, two proteins that can be targeted with drugs to enhance the survival of mantle cell lymphoma patients were identified. These proteins will be the focus of future studies to improve survival of mantle cell lymphoma patients. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9055309
- author
- Andersson, Stina LU
- supervisor
- organization
- course
- KIMM05 20211
- year
- 2021
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9055309
- date added to LUP
- 2021-06-18 14:30:19
- date last changed
- 2021-06-18 14:30:19
@misc{9055309,
abstract = {{Mantle cell lymphoma (MCL) with Myc aberrations has previously been shown to be associated with poor survival and worse response to current treatment strategies. This study aims to investigate the association between Myc overexpression and clinical outcome and to identify drugs targeting MCL with Myc alterations. Data from the two patient cohorts BLISS and N-MCL2/3 was analyzed, and the association between Myc status and patient characteristics was evaluated. Results from a drug screening on six MCL cell lines were analyzed with respect to how the drugs targeted the cell lines with Myc and/or p53/TP53 aberrations. Our data confirmed that Myc overexpression is indeed associated with worse prognosis. We also identified a subgroup of patients with tumors that both overexpressed Myc and had p53/TP53 aberrations that was associated with a survival even worse than patients with tumors overexpressing Myc or having p53/TP53 aberrations alone. In addition to p53/TP53 aberrations, Myc overexpression was significantly correlated to non-classic morphology, high Ki67 expression, age, and reduced expression of CD8 positive cells. The two kinases PLK1 and Wee1 induced cell death in both the cell lines with Myc overexpression and the cell lines with p53/TP53 mutations. They also reduced cell proliferation in the cell lines overexpressing Myc. Therefore, PLK1 and Wee1 are considered possible drug target candidates in MCL with Myc aberrations.}},
author = {{Andersson, Stina}},
language = {{eng}},
note = {{Student Paper}},
title = {{Analysis of Myc Aberrations in Mantle Cell Lymphoma and Drug Target Identification}},
year = {{2021}},
}