Chromosomal Abnormalities In Lymphoproliferative Disorders (Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia)

Chromosomal Abnormalities In Lymphoproliferative Disorders

Leukemias are clonal hematopoietic neoplastic diseases, originate from an abnormal stem cell. In the course of biological evolution, cancer cells undergo a gradual change of genotype, resulting in mutant cells. Cytogenetic analysis represents a major tool for investigating the biology of cancer because it offers the most valuable information. Karyotype is a useful tool for monitoring patients with leukemia.

Acute Lymphoblastic Leukemia (ALL)

It is the most common type of leukemia that occurs in childhood. Chromosomal abnormalities are present in most patients with acute lymphoblastic leukemia (ALL).

One of the features of ALL in children is increased incidence of hyperdiploidy, which usually includes trisomies of chromosomes 4, 6, 10, 17, 18, 20, 21. Hyperdiploidy with more than 50 chromosomes is associated with a favorable outcome (cure up to 90% by conventional therapy), while a modal number below 50 chromosomes confers a poor prognosis.

Hypodiploidy in acute lymphoblastic leukemia is rare, however, a massive loss of chromosomes that is leading to modal number of maximum 24 chromosomes is almost exclusively found in ALL and in lymphoid form of blast crisis of chronic myeloid leukemia.

About 30% of leukaemic cells in adults with ALL have a pseudodiploid constitution (46 chromosomes but with structural rearrangements).

Karyotype instability is a phenomenon that occurs frequently in acute lymphoblastic leukemia. During relapses, 30% -80% of patients present a variety of additional or structural modifications superimposed or derived from the original  modifications. The most common structural rearrangements are the translocations.

Acute Lymphoblastic Leukemia Karyotype

In B-cell acute lymphoblastic leukemia are more common translocations between chromosomes 9 and 22 (Philadelphia chromosome), translocations between chromosomes 4 and 11 and translocations between chromosomes 1 and 19.

Philadelphia chromosome (translocation between chromosomes 9 and 22) occurs in 17% of ALL cases in adults and only 5% of ALL in children and has the same morphological aspects as in chronic myelogenous leukemia. Molecular analysis revealed that Philadelphia chromosome break point on chromosome 22 is located more proximally than that involved in the formation of Philadelphia chromosome in chronic myelogenous leukemia. By molecular analysis were revealed fusions between  BCR gene (breakpoint cluster region, located on chromosome 22) and ABL gene (abelson murine leukemia, located on chromosome 9) in about 30% of patients with ALL. Translocations between chromosomes 9 and 22 are associated with hyperleukocytosis and is a factor of poor prognosis (life expectancy is 15 months).

In patients with T cell acute lymphoblastic leukemia were observed chromosomal rearrangements involving the genes that encode T cell receptors:

• TCRA and TCRD on chromosome 14;
• TCRB and TCRG on chromosome 7.

So far, these translocations have been described as specific for T-cell acute lymphoblastic leukemia:

• Translocations between chromosomes 8 and 14;
• Translocations between chromosomes 11 and 14;
• Translocations between chromosomes 10 and 14;
• Translocations between chromosomes 1 and 14;
• Translocations between chromosomes 7 and 19.

Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia is the most common type of leukemia, accounting for 30% of all leukemias. Is more common in men aged over 60 years.

Although the etiology is unknown, the involvement of genetic factors is evidenced by:

• High familial incidence;
• Coexistence of CLL with autoimmune diseases or malignant tumors;
• Certain areas of the world are endemic for leukemia / lymphoma with T cells produced by infection with a lymphotropic retrovirus ( RNA virus), HTLV 1 (Human T Leukemia / Lymphoma Virus 1).

In chronic lymphatic leukemia, in over 95% of the cases appear a clonal expansion of B cell line and in less than 5% of the cases appear a clonal expansion of malignant cells with T phenotype.

Chronic Lymphocytic Leukemia

In 50% of patients with CLL are identified chromosomal abnormalities. At the onset, the most common chromosomal abnormality is trisomy 12, this situation represents a factor of good prognostic, patients having a longer disease-free survival.

In advanced stages appear other chromosomal abnormalities, the most common being  rearrangements of chromosome 14 or translocations between chromosomes 11 and 14. On chromosome 14 are localized the gene responsible  for immunoglobulin heavy chain synthesis and the gene responsible for synthesis of alpha chain T cells receptor. Translocation between chromosomes 11 and 14 activate bcl1 oncogene (B cell lymphoma / leukemia 1), located on chromosome 14, gene that encodes BCGF protein (a protein that acts as a B cell growth factor). Patients with chronic lymphocytic leukemia who have chromosomal abnormalities have a lower survival rate.

A special type of chronic lymphocytic leukemia is the type associated with ataxia-telangiectasia (a genetic disorder characterized by progressive cerebellar degeneration), in which translocations occur between chromosomes 14.