Page 1461 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 81

MANTLE CELL LYMPHOMA

Vijaya Raj Bhatt, Roberto Ferro Valdes, and Julie M. Vose

INTRODUCTION ataxia telangiectasia mutated (ATM) genes. The vast majority of
MCL have the reciprocal translocation, t(11;14) (q13;q23), which
Mantle cell lymphoma (MCL) is a distinct subtype of mature B-cell juxtaposes CCND1 gene to the immunoglobin heavy-chain locus.
non-Hodgkin lymphoma (NHL) that accounts for 5–10% of all The consequent overexpression of CCND1 gene located at 11q13
NHL. Although a subset of patients with MCL may have an indolent encodes cyclin D1 protein. Cyclin D1 protein, which is not expressed
course, MCL is generally an aggressive NHL. In the 1970s, the Kiel in normal lymphocytes, is expressed in virtually all MCL, and at a
classification used the terminology centrocytic lymphoma to describe lower level in Burkitt lymphoma and acute lymphoblastic lymphoma
MCL, whereas Berard and Dorfman categorized it as lymphocytic (ALL). A few cells with t(11;14) have been found in the blood of
lymphoma of intermediate differentiation. In the 1980s, the term 1–2% of healthy individuals. Therefore, cyclin D1 overexpression is
mantle zone lymphoma was used to denote a distinct subtype of MCL not sufficient for the transformation of normal B cells to MCL, rather
characterized by the proliferation of atypical small lymphoid cells it is thought to represent an early genetic event. Interestingly, the
with wide mantles around benign germinal centers (GCs). In the close physical proximity of the chromosomal regions of the IgVH
Revised European-American Lymphoma classification in 1994 and and CCND1 loci in the nucleus of immature lymphoid B cells may
later in 2001 and 2008, the WHO classification of tumors of hema- facilitate the occurrence of recurrent translocations. Furthermore,
topoietic and lymphoid tissues recognized MCL as a distinct disease colocalization and interaction of IgVH-CCND1 chromosomal
under mature B-cell lymphomas. With the recognition as a distinct segment and a transcription factor called nucleolin near the perinu-
entity, in recent years, significant progress has been made toward cleolar area leads to the transcription of cyclin D1 protein. Cyclin
understanding the underlying pathogenesis of MCL and translating D1 protein then regulates the G1 phase by binding to cyclin-
that knowledge to design more effective therapies. 1 dependent kinase (CDK) 4 and CDK6. The cyclin D1-CDK complex
phosphorylates retinoblastoma 1 (RB1) resulting in a release of E2F
transcription factor, and transition of a cell from G1 to S phase.
EPIDEMIOLOGY Additionally, the CDKN2A gene on chromosome 9p, which regulates
INK4a protein, is deleted in 20–30% of highly proliferating MCL.
MCL is two- to sevenfold more common in men than women and The INK4a protein inhibits CDK4 and CDK6, and thus maintains
almost twofold more common in whites than African Americans. The the RB1 protein in its active, antiproliferative state. INK4a is fre-
average age at diagnosis varies between 60 and 70 years. The annual quently deleted in MCL and cooperates with CCND1 gene. There-
incidence is approximately 4 to 8 cases per million population in the fore, the CDKN2A-INK4a-CDK4-RB1 pathway is dysregulated in
United States and Europe. patients with MCL, particularly those with blastoid histology. 2
Recent studies have described cyclin D1-negative MCL cases that
demonstrate pathologic features and gene expression profile similar to
PATHOBIOLOGY cyclin D1-positive MCL. Cyclin D1-negative MCL is associated with
the dysregulation in the expression of the following genes, often due
MCL, characterized by an alteration in the regulation of the cell- to epigenetic changes: overexpression of cyclin D2 or D3; decreased
cycle, demonstrates cyclin D1 overexpression and increased replica- CDK inhibitor 1B (CDKI1B or p27); upregulation of cyclin E; or
tion. The tumor cells also demonstrate decreased response to DNA inactivation of RB gene. CDKI1B protein regulates the cell progres-
damage and resistance to apoptosis. The tumor cells originate from sion from G1 to S phase by inhibiting the cyclin E/CDK2 complex
pre-B cells in the bone marrow that can follow at least two different (the latter also inactivates the RB protein). Although the diagnosis of
molecular pathways of development. cyclin D1-negative MCL is uncommon and requires caution, these
The classical MCL originates from a naive B cell that has not cases highlight the relevance of the oncogenic dysregulation of the cell
entered the follicular GC, but has SOX11 expression, lambda light cycle, especially of the G1 phase in the pathogenesis of MCL.
chain restriction, and limited or no immunoglobulin heavy chain
variable (IgVH) somatic mutations. SOX11 expression is associated
with the activation of histone marks and absence of DNA methyla- Antiapoptotic and Prosurvival Pathways
tion. The second subset of MCL, an indolent form typically limited
to peripheral blood and spleen, originates from post-GC B cells. This Some patients with aggressive MCL, particularly the blastoid variant,
MCL subset has frequent IgVH mutations, typically lacks SOX11 have an increased number of chromosomal abnormalities, such as
expression, and has kappa light chain restriction. A few studies have complex karyotype and tetraploidy. The accumulation of chromo-
demonstrated a correlation between SOX11 expression and aggressive somal abnormalities suggests alterations in the DNA damage response
tumors with high serum levels of lactate dehydrogenase (LDH) and pathways. TP53 mutation and deletion or point mutation of the
high Ki-67 index. Conversely, SOX11-negative MCL may occasion- ATM gene (located at11q22-q23) are recurrent mutations in MCL.
ally acquire complex karyotype and TP53 alterations and transform TP53 mutations, associated with alterations of 17p chromosomal
into aggressive tumor (Fig. 81.1). segment, are present in 10% to 28% of MCL cases. These point
mutations are frequently missense mutations that compromise
normal p53 expression. The TP53 tumor suppressor gene normally
Genetic Alteration of Proliferative Pathways regulates the cell cycle, DNA repair, apoptosis, senescence, and
autophagy through transcription-dependent and independent path-
The three most common recurrent mutations in MCL involve ways. Disruption in TP53-dependent apoptosis has also been linked
CCND1 (also known as Cyclin D1, BCL1, or PRAD1), TP53, and to deletion, mutation, or silencing of BIM and NOXA genes. The

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