Etiology of MDS

Advances have occurred in the understanding of myelodysplastic syndromes (MDS) over the past decade; however, the etiology of MDS still is not fully understood.1, 2

It is well-established, though, that MDS is a disorder characterized by cytogenetic abnormalities that cause highly productive but dysplastic hematopoiesis, involving myeloid, erythroid and megakaryocyte cells.3, 4 MDS has been widely described, therefore, as a disease of ineffective rather than insufficient hematopoiesis.4

The pathogenesis of MDS is a multi-step process that begins when the bone marrow spontaneously produces dysplastic myeloid stem cells. This dysplastic hematopoiesis has been assumed to result from mutations that cause chromosomal defects,4 typically additions or deletions.4 The defects are then passed on to the myeloid stem cells' progeny. The most common cytogenetic abnormalities are a loss or gain of part or all of chromosomes 5, 7, 8 and 20.4

Three processes of dysplastic hematopoiesis have great influence on the blood and marrow profile:

• Profuse production5
• Apoptosis6
• Impaired maturation (the most definitive feature)4

The neodysplastic myeloid cells produce rapidly and somehow achieve an advantage over normal myeloid cells in succeeding and differentiating generations.5

Along with the profuse hematopoiesis, there is extensive apoptosis, which arises from condensation, fragmentation and chromatin clumping in the nucleus.6 As the apoptosis and dysplastic hematopoiesis proceed, the population of dysplastic cells in the blood and marrow climbs while the population of normal cells declines.5

Also, as the dysplastic cells progress toward differentiation, many of them stall in the maturation process, creating a population of stranded myeloid blasts.4

Ultimately the blood and marrow profile is characterized by much higher than normal numbers of myeloid cells, higher than normal numbers of myeloid blasts, and high levels of apoptosis of healthy cells.4

The dysplasia can involve any or all of the three cytogenetic lineages and can develop in a variety of forms and with a variety of courses. The point in the myeloid cell maturation process at which the dysplasia occurs determines the subsequent biology of the disease.4 How many lineages are involved, the number of blasts in the blood and marrow, and other factors determine the disease type.5

Currently the cause of the spontaneous genesis of MDS is unknown. Primarily MDS arises de novo, but in 10%-20% of cases it is secondary to chemotherapy.5 Alkylating agents are commonly associated with abnormalities in chromosomes 5 and 7.3 MDS also can arise secondary to radiation. But whether it occurs de novo or secondary to therapy, the cytogenetic problems are very similar.3 Significant exposure to environmental toxins, including pesticides and organic solvents like benzene, also has been linked with MDS development.5

As new diagnostic tools like fluorescence in situ hybridization (FISH) and polymerase-chain-reaction (PCR) analysis are used to study MDS, more and better information on the disease is emerging.