Myeloproliferative disorders are clonal hematopoietic neoplastic diseases that originate from an abnormal stem cell. In all myeloproliferative disorders the proliferation capacity of abnormal stem cell is not adequately controlled and for this reason an excessive and ineffective hematopoiesis occurs. One of the neoplastic stem cell characteristic is to maintain its differentiation capacity and therefore, in peripheral blood is an increased number of mature and immature neoplastic cells.
Detection of chromosomal abnormalities by cytogenetic techniques continues to be a major instrument in the investigation of malignant hematological disorders because can provide important information about diagnosis, evolution and prognosis of the disease.
These molecular cytogenetic tests can detect chromosomal anomalies and hybrid oncogenes and can also determine the exact percentage of malignant cell clones.
Myelodysplastic Syndromes (MDS)
Myelodysplastic syndromes are considered preleukemic syndromes, situated at the boundary between refractory anemia and acute myelogenous leukemia. MDS occur more frequently in adults, over the age 50 years.
According to FAB classification (French American British) myelodysplastic syndromes are divided into:
- Refractory anemia;
- Refractory anemia with ringed sideroblasts;
- Refractory anemia with excess blasts;
- Refractory anemia with excess blasts and in transformation;
- Chronic myelomonocytic leukemia (CMML).
Clonal chromosomal abnormalities (monosomies, trisomies or structural abnormalities) can be seen at the initial cytogenetic analysis of bone marrow or as a result of karyotype evolution during disease progression.
Main karyotype changes refer to a loss of genetic material:
- Deletions of long arm of chromosome 5 or chromosome 7;
- Partial monosomy of chromosome 5 or chromosome 7;
- Total monosomy of chromosome 5 or chromosome 7.
Chromosomes 5 and 7 are known as carriers of various oncogenes and deletions at their level may lead to their alteration and consecutive appear neoplastic growth factors that lead to abnormal clones proliferation.
Chromosomal abnormalities are not specific associated with a particular group of FAB classification, except for deletion of long arm of chromosome 5 that is associated with refractory anemia.
Evolution of patients with MDS to acute myeloid leukemia occurs mostly in cases where there are total monsomy of chromosomes 5 and 7 or in the case of multiple chromosomal abnormalities. Increased complexity of genetic abnormalities was correlated with a short survival and probably reflects the expansion of unstable genetically clones.
In children with myelodysplastic syndromes most commonly encountered are trisomy 8, monosomy 7, deletions of the long arm of chromosome 20 and deletions of the long arm of X chromosome. Total monosomy of chromosome 7 is specific for children with myelodysplastic syndromes and indicate a poor prognosis.
Patients with myelodysplastic syndromes and a normal karyotype have a better survival. Highlighting an unstable karyotype indicates a poor prognosis.
Acute Myeloid Leukemia (AML)
Most patients present clonal chromosomal abnormalities, along with cells with normal karyotype. Chromosomal abnormalities observed at disease onset disappear in complete remissions and reappear shortly before relapse.
FAB (French American British) classification of acute myeloid leukemia includes 8 subtypes and it is conceived upon morphological, enzymatic and immunological criteria. Due to constant and specific association of certain chromosomal abnormalities with morphological subtypes, some of the chromosomal abnormalities are assigned as complementary quality criteria for the classification of acute leukemia.
Subtype M0 (minimally differentiated acute myeloblastic leukemia): most patients present a single cytogenetic abnormality, of which the most common is trisomy 7 or total monosomy of chromosome 7. Prognosis of these patients is reserved, compared with other subtypes of FAB classification.
Subtype M1 (acute myeloblastic leukemia, without maturation): most are secondary leukemias with very severe prognosis and the most commonly encountered type of cytogenetic abnormalities are the loss of genetic material, for example total monosomy of chromosome 7. Philadelphia chromosome can be identified in some cases of M1 subtypes and indicate a very severe prognosis.
Subtype M2 ( acute myeloblastic leukemia, with granulocytic maturation): most patients have translocations between chromosomes 8 and 21. At the breaking point on chromosome 21 is located AML1 gene(acute myeloid leukemia 1), and at the breaking point of chromosome 8 is located MTG8 gene (myeloid translocation on 8). After translocation of these two chromosomes appear a hybrid gene called AML1/MTG8 which product seems to be the critical event in cancer cell proliferation. Among numerical chromosomal abnormalities found in AML, the most common is trisomy 8, which is correlated with this subtype and indicate a good prognosis. Other chromosomal abnormalities are represented by translocations between chromosomes 22 and translocations between chromosomes 6 and chromosome 9.
Full remission is achieved in 90% of cases and average survival is about 2 years.
Subtype M3 ( promyelocytic or acute promyelocytic leukemia ): translocation between chromosome 15 and chromosome 17 is considered to be the most specific chromosomal abnormality and is associated exclusively with M3 subtype, being present at about 100% of patients. Genes isolated from the breaking points are PML (promyelocytic leukemia) on chromosome 15 and RARA (retinoic acid receptor alpha) on chromosome 17. Protein encoded by hybrid gene PML / RARA inhibit cellular differentiation and determine clonal expansion of promyelocytes. Translocation between chromosomes 15 and 17 indicate a good prognosis because it was identified a specific therapy with retinoic acid that induces cell differentiation process, thus overcoming the stage of promyelocytes.
Subtype M4 (acute myelomonocytic leukemia): presents different structural abnormalities on chromosome 16, such as inversions, deletions and translocations between chromosomes 16. Patients with structural abnormalities of chromosome 16 have a better prognosis compared with patients in which chromosome 16 is normal.
Subtype M5 subtype (acute monocytic- monoblastic leukemia): among cytogenetic abnormalities found in this subtype most commonly are observed changes in the long arm (q) of chromosome 11, region 23 (translocations involving 11q23 and another chromosome, followed by interstitial or terminal deletions).
Molecular studies have isolated in the region 11q23, gene MLL (myeloid-lymphoid leukemia), which encodes “zinc finger” domains that bind DNA, which requires its inclusion in the category of genes that are regulating cell differentiation process.
In order of frequency, translocations involving 11q23 region are:
- Translocations between chromosomes 9 and 11;
- Translocations between chromosomes 11 and 19;
- Translocations between chromosomes 6 and 11;
- Translocations between chromosomes 1 and 11.
Structural rearrangements in the 11q23 region are associated with a poor prognosis.
Subtype M6 (acute erythroid leukemia) is a rare form of AML, characterized by the presence in the bone marrow of dysplastic erythroblasts. This subtype is characterized by complex cytogenetic abnormalities and by chromosomal karyotype instability.
Subtype M7 (acute megakaryoblastic leukemia): although chromosomal abnormalities in this subtype are nonspecific, were observed aberrations of chromosome 3, inversions or deletions of this chromosome have a higher incidence when there is present an abnormal megakaryocytopoiesis.