GENETICS OF MULTIPLE MYELOMA
The MM is a malignant tumor of germ post-centro B cells. Neoplastic cells are characterized by mutations in regions varying from heavy chains (IgH) and light (IgL) immunoglobulin, somatic hypermutation and antigenic selection processes as a result.
The majority of tumors present IgH chain isotype switch and expressed most frequently IgG and IgA and rarely IgD and IgE. Very infrequently expressed only IgM (1%) and up to 15% of cases express only light chains.
One of the main genetic characteristics of MM is the presence of translocations involving the locus of IgH (14q32) or one of the loci of IgL (Igk 2pl2 e Igd 22q11). It is thought that these translocations result from errors in one of the three specific processes of the B cells that modify DNA:
- VDJ recombination;
- somatic hypermutation and
- IgH isotype switch.
The consequence of these translocations is deregulation or increased expression of an oncogene that is positioned near one or more regulatory segments (enhancers) Ig genes.
An initial event at the root of many cases of MM is the chromosomal translocation involving the regions switch of IgH (14q32) gene and several other non-randomized regions, in which they have located the genes of the family of the ticunas D (cyclin D3 6p21, cyclin DI 11q13), members of the MAF family (c-MAF 16q23, MAFB 20q12) and fibroblast growth factor receptor 3 (FGFR3 4p16).
These recurrent translocations have been identified in approximately 50% of primary samples from patients with MM. The other half of the patients is characterized by the presence of multiple trisomies (hiperdiploidia), most commonly of chromosomes 3, 5, 7, 9, 11, 15, 19, 21.
The oncogenic evolution of the hiperdiploide group are least understood. These primary or early genetic events (translocations of IgH and hiperdiploidia) have in common the overexpression of one or more ticunas {(D1-D3) D on the almost all of the patients with MM by what has been proposed that the overexpression of cyclin D is an event keyword in the pathogenesis of the MM.
After these primary genetic alterations the progression of the disease is characterized by the occurrence of side events (translocations, deletions and mutations) consequence of genomic instability of neoplastic cells.
These include the monosomy/deletion of chromosome 13, the deletion of chromosome 17 and sees the amplification of chromosome 1, all with important implications.
Other common genetic disorders are somatic mutations in genes such as P53 (with consequent loss of function), FGFR3, NRASy KRAS (producing overactivation in all 3 cases) or other secondary translocations arising through mechanisms not involved in the differentiation of b cells.
A region that is commonly present in secondary translocations is the 8q24, where MYC gene is located.
Multiple myeloma is characterized by several features including:
- Low blood counts
In multiple myeloma, the excessive proliferation of plasma cells in the bone marrow can displace cells producing normal blood cells, causing low blood counts. This can cause anemia (a shortage of red blood cells).
People who have anemia have paleness, weakness and fatigue. Multiple myeloma can also cause a low level of platelets in the blood (thrombocytopenia). This can cause an increase in bleeding and appearance of bruising. Another condition that can occur is leukopenia (lack of normal white blood cells), which can cause problems to fight infections.
- Problems with the bones and calcium
Myeloma cells also interfere with the cells that help keep bones strong. Bones are constantly rebuilding to remain strong.
Usually, the two main classes of bone cells work together to keep your bones healthy and strong. Call the cells that generate new bone osteoblasts, while that cells dissolving old bone called osteoclasts. Myeloma cells produce a substance that tells the osteclastos that accelerate the dissolution of the bones. Since osteoblasts do not receive a signal to let the new bone, old bone disintegrates while new bone to replace it.
This weakens the bones and cause that break easily. Bone fractures are one problem in people with myeloma. This increase in the degeneration of the bones can also increase calcium levels in the blood. Problems caused by high levels of calcium are discussed in the section.
- Infections
The abnormal plasma cells do not protect the body from infections. As mentioned previously, the normal plasma cells produce antibodies that attack germs.
For example, if you get pneumonia, normal plasma cells produce antibodies that are directed to the specific bacteria that were causing the disease. These antibodies help the body attack and eliminate bacteria. In multiple myeloma, myeloma cells displace the normal plasma cells so that the antibodies may not occur to fight infection.
Antibody producing myeloma cells does not help fight infections. This is because myeloma cells are only multiple copies of the same plasma cell (all producing copies of the same antibody.
- Kidney problems
Antibody producing myeloma cells may cause damage to the kidneys. This can lead to damage in the kidneys and even kidney failure.