Cytogenetics and molecular genetics of acute lymphoblastic leukemia

Abstract

An important factor in the diagnosis of acute lymphoblastic leukemia (ALL) is that karyotype is an independent prognostic indicator, with an impact on the choice of treatment. Outcome is related to the number of chromosomes. For example, high hyperdiploidy (51-65 chromosomes) is associated with a good prognosis, whereas patients with near haploidy (23-29 chromosomes) have a poor outcome. The discovery of recurring chromosomal abnormalities in the leukemic blasts of patients with ALL has identified a large number of genes involved in leukemogenesis. Certain specific genetic changes are related to prognosis. The ETV6/AML1 fusion arising from the translocation (t12;21) (p13;q22) has been associated with a good outcome; the BCR/ABL fusion of (t9;22)(q34;q11), rearrangements of the MLL gene, and abnormalities of the short arm of chromosomes 9 involving the tumor suppressor genes p16INK4A have a poor prognosis. Unfortunately, the classification of patients into prognostic groups based on cytogenetics is not always as predicted. Even when other clinically based risk factors are taken into account, some patients with good-risk cytogenetic features will relapse. In the search for new measures of prognosis, it has recently emerged that the level of minimal residual disease following induction therapy can be a reliable predictor of outcome in ALL.

Importance of FISH combined with Morphology, Immunophenotype and Cytogenetic Analysis of Childhood/Adult Acute Lymphoblastic Leukemia in Omani Patients

“…In our study, the bone marrow cultures for nine patients either yielded no metaphases or the quality of the chromosomes was too poor with clumped metaphases, which is commonly known in most of the ALL cases (Petkovic et al, 1996) and the percentage of diploid karyotype (25.8%) presently tended to decrease compared to the earlier years, likely attributable to technical progress such as improvement of culture conditions, cell synchronization, and the introduction of integrated FISH screening method may have led to a higher incidence rate of chromosomal abnormalities in our study similar to previous studies (Hashem, 2012). The presence of normal metaphases could be explained as residual normal cells, the marrow infiltration by leukemic blasts being usually partial; it could also be the result of the low mitotic rate of the blast cells (Harrison and Faroni, 2002).…”

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

“…In United States this is estimated to be 17-25% among pediatric patients (Loh et al, 1998;Jamil et al, 2000). The incidence of TEL-AML1 fusion in 334 Italian and German children with ALL was 18.9% (Borkhardt et al, 1997) and 22-27% in German children alone (Papadhimitriou et al, 2008), as compared to 22.5% in 617 children from UK (Harrison, 2000). Similarly the prevalence of TEL-AML1 transcript in acute lymphoblastic leukemia patients in Serbia is 17.1% (Lazic et al, 2010) and 20% in Brazil (Magalhaes et al, 2000).…”

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…These include high hyperdiploidy, hypodiploidy, the translocations t(12;21)(p13;q22)[ETV6-RUNX1], t(1;19)(q23;p13.3) [TCF3-PBX1], t(9;22)(q34;q11)[BCR-ABL1] and rearrangement of the MLL gene at 11q23 in B-progenitor ALL, rearrangement of MYC in mature B-cell leukemia/lymphoma, and rearrangement of the TLX1 (HOX11), TLX3 (HOX11L2), LYL1, TAL1 and MLL genes in T-ALL. [8][9][10][11][12] These translocations frequently involve transcriptional regulators of hematopoiesis and are important initiating events in leukemogenesis, but the observations that these abnormalities are often detectable years before the onset of leukemia and usually do not alone result in leukemia in experimental models 13,14 suggest that cooperating genetic or epigenetic lesions are required. Candidate gene studies have identified lesions such as deletion of the CDKN2A/CDKN2B (encoding the tumor suppressors p16INK4A, p14ARF and p15INK4B) and NOTCH1 in T-ALL, [15][16][17][18] but until recently methods to analyze genetic alterations in a genome-wide fashion have been lacking.…”