Cancer remains one of the most challenging adversaries of our time. Each year it claims millions of lives around the globe, igniting a battle that tests the limits of science, resilience, and hope. There are many types of cancer depending on the body part or organ where it originates from. One of the most common types of cancer among people worldwide is called Lymphoma.

Lymphoma is a type of cancer that affects the lymphatic system. The lymphatic system is a part of the immune system and involves the body fluid called lymph. It involves organs like the spleen, thymus, tonsils, lymph nodes, bone marrow and certain mucous membranes. Lymphomas are further divided into categories, one of them being the Mantle Cell Lymphoma (MCL).

This article involves a detailed explanation of Mantle Cell Lymphoma and how the genetics of a person play an important role in the development of the disease. Additionally, diagnosis and treatment strategies are also discussed.

Introduction

Definition of mantle cell lymphoma 

Mantle Cell Lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma (NHL) that mainly involves B lymphocytes. It usually arises from the outer edge of the lymph node follicle, known as the mantle zone. Hence it is named mantle cell lymphoma. MCL is typically sporadic in nature and comprises 5% of all cases of NHL. Symptoms include swollen lymph nodes, fever, night sweats, and weight loss. It can also affect the spleen, bone marrow, and gastrointestinal tract.¹  

Importance of understanding the molecular and genetic basis of mantle cell lymphoma 

Understanding the molecular and genetic basis of MCL is crucial for a better understanding of the disease and improving its prognosis and treatment. Genetic mutations like chromosomal translocation t(11;14) lead to overexpression of cyclin D1 (CCND1) genes that are responsible for MCL. Knowledge of such genetic mutations helps in differentiating MCL from other lymphomas and assists in better prognosis and treatment. Molecular insights guide the development of targeted therapies, improving treatment efficacy and reducing side effects.¹

Basic concepts

Overview of lymphoma

Lymphomas originate from the lymphatic system and are broadly classified into two categories:

Hodgkin lymphoma 

Hodgkin lymphoma (HL) is characterised by the presence of Hodgkin Reed-Sternberg (HRS) cells that originate from B lymphocytes. Histologically, HRS are large, bilobed cells with two nuclei. HL is further divided into two classes, namely, classic HL (cHL) and non-classic HL

Classic HL is the most common type of lymphoma that is further of four different types: nodular sclerosing, mixed cellularity, lymphocyte rich, and lymphocyte depleted. Non-classical HL is of only one type, nodular lymphocyte-predominant.² 

Non-hodgkin lymphoma 

NHL comprises diverse types of lymphoma based on the type of lymphocyte involved. There are over 60 such subtypes but some of the common ones have been mentioned below:

• B-cell Lymphomas: As the name suggests, these lymphomas involve cells that have originated from B lymphocytes. These involve diffuse large B-cell lymphoma (DLBCL) which is the most common subtype of NHL, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, marginal zone lymphomas and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL)
• T-cell Lymphomas: These include cells that arise from T lymphocytes and comprise many different types like Peripheral T-cell lymphomas (PTCL), Cutaneous T-cell lymphomas (CTCL), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell Lymphoma (AITL)²

Cellular origin of mantle cell lymphoma

Description of mantle zone B-cells

The mantle zone of a lymphoid follicle refers to an outer layer that surrounds the germinal centre. The B lymphocytes present in this zone are called the mantle zone B-cells. The germinal centre is the part of the follicle where the B cells divide and differentiate whereas the surrounding mantle zone consists of naive B cells. 

Mantle zone B cells are called naive B cells as they have not encountered any antigen yet. They circulate between the blood, lymphoid tissues, and secondary lymphoid organs, ready to respond to pathogens.³ 

Role of B-cells in immune function

B cells or B lymphocytes play a major role in adaptive immune response against pathogens. The B cells perform an array of functions and the major one includes antibody production against the specific antigens. Common antibodies produced by B cells are IgM, IgA, IgG, IgE and IgD. Antigen presentation is another function in which B cells present antigens to the T cells that lead to T cell activation. Other common functions involve cytokine production that leads to inflammation and immunological memory with the help of memory B cells.⁴  

Genetic alterations & molecular pathways involved in mantle cell lymphoma

Key genetic mutations

Certain genetic mutations are observed among patients diagnosed with MCL. The hallmark genetic instability of MCL is the translocation between chromosome 11 and chromosome 14 referred to as t(11;14) (q13;q32). This leads to the juxtaposition of the cyclin D1 (CCND1) gene from chromosome 11 to the immunoglobulin heavy chain locus on chromosome 14.

This translocation results in overexpression of the CCND1 gene and excessive production of cyclin D1 protein. Cyclin D1 protein is a cell cycle regulator that helps in cell division. Too much of this protein causes uncontrolled proliferation which is a key feature of MCL.⁵  

Secondary genetic events

Apart from the above aforementioned genetic mutations, many other genetic aberrations can be responsible for cases of MCL. One of them is overexpression of the SOX11 gene. SOX11 is a neural transcription factor that is excessively produced in many cases of MCL. Although there is no precise knowledge of its role and mechanism, SOX11 leads to an aggressive MCL as it promotes cell proliferation and survival. SOX11 is also used as a diagnostic marker in certain cases.⁶  In rare cases of mantle cell lymphoma (MCL), the overproduction of cyclin D2 and cyclin D3 proteins can also occur.

 This occurs due to the upregulation of CCND2 and CCND3 genes respectively. These cyclins can also contribute to the uncontrolled proliferation of B-cells in MCL.¹ 

Another type of cell cycle protein called cyclin-dependent kinases (CDK) can also contribute to MCL in some cases. CDK4 and CDK6 amplification enhances cell cycle dysregulation in MCL, supporting the uncontrolled growth of malignant cells. Additional genetic mutations include MYC which is an oncogene and BCL2 and BCL6 which are involved in a cell death mechanism known as apoptosis.⁷ 

DNA damage response

Ataxia-telangiectasia mutated (ATM) gene is involved in DNA damage response and repair. Mutation or inactivation in the ATM gene is quite frequent in MCL patients as it causes defective DNA repair mechanisms, contributing to genomic instability and alterations.⁸ Another gene that is involved in DNA repair pathways is the TP53 gene

TP53 is a tumour suppressor gene that encodes for p53 protein which is a tumour suppressor protein. As the name suggests, this protein suppresses tumour growth and plays a crucial role in DNA repair, cell cycle regulation, and apoptosis. However, mutations in the TP53 gene result in the production of defective p53 protein, thereby allowing cells with damaged DNA to survive and proliferate.⁹ 

Signalling pathways

Signalling pathways play an important role in transferring chemical signals between cells. They are responsible for controlling cell functions like cell division or cell death. Many signalling pathways are involved in MCL. One of the major ones is the NOTCH signalling pathway which plays a role in cell differentiation, proliferation, and apoptosis. Mutations in NOTCH1 and NOTCH2 proteins may promote division and growth of malignant B cells in MCL.¹⁰ 

Other signalling pathways contributing to MCL pathogenesis include the PI3K/AKT/mTOR pathway that is responsible for tumour proliferation and survival. WNT, Hedgehog, and NF-κB pathways also play a role in MCL pathogenesis.⁷ 

Diagnosis and treatment of mantle cell lymphoma

Diagnosis

Diagnosis of MCL comprises several laboratory tests, clinical evaluation and imaging techniques. For clinical evaluation, the doctor evaluates the medical history of the patient and conducts a physical examination that focuses on identifying swollen lymph nodes or swollen liver or spleen. Imaging studies like Computed Tomography (CT) scan, Positron Emission Tomography (PET) scan or Magnetic Resonance Imaging (MRI) are also used for diagnostic purposes. Several blood tests like complete blood count (CBC) and biopsies like bone marrow aspiration and lymph node biopsy are also conducted for diagnosis and assessment of lymphoma cells.¹

Treatment strategies

The Treatment strategy for MCL mainly involves different combinations of chemotherapy. First-line chemotherapy involves drugs like Doxorubicin, Vincristine Rituximab and combinations of Bendamustine with Rituximab which gives better efficacy. Immunotherapy is another common option which involves administering monoclonal antibodies like Obinutuzumab or checkpoint inhibitors like Pembrolizumab and Nivolumab. 

Targeted therapy is another strategy which involves focusing on inhibiting a specific signalling pathway or molecule to prevent tumour growth. Bruton’s Tyrosine Kinase (BTK) inhibitors, BCL-2 inhibitors and PI3K inhibitors are common drug types of targeted therapy. Lastly, stem cell transplantation is also used usually combined with a high-dose chemotherapy.¹¹ 

Summary

• Lymphomas are the cancer of the lymphatic system and it consists of many subtypes 
• Broadly, it is classified into Hodgkin lymphoma and Non-Hodgkin lymphoma. Mantle Cell lymphoma is a type of NHL
• Many genetic mutations and instabilities in certain signalling pathways can trigger the uncontrolled cell proliferation of malignant B cells
• Many diagnostic methods like biopsies and imaging techniques are widely used for prognosis

Treatment methods involve chemotherapy, immunotherapy, targeted therapy and stem cell transplantation.