Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Scientific Background

ALL is caused by a neoplasm of lymphoblasts. A differentiation is made between B-ALL (approx. 75-85% of all cases) and T-ALL (approx. 15-25% of all cases). 75% of all ALL cases occur in children under 6 years of age; the incidence is 1–4.75:100,000/year.

The classification of ALL is primarily based on the immunophenotype of the blasts. The expression of different antigenes is determined on the surface or in the cytoplasma of the blasts. Depending on the degree of differentiation, B-ALL is classified as pro-B, common, pre-B and mature B-cell ALL, while T-ALL is classified as early, thymic and mature T-ALL. In the majority of all B-ALL cases cytogenetic abnormalities are observed, which allow stratification into a certain clinical subgroup with a clear phenotype and prognostic features .

In approx. 25% of all affected adults and in 2-4% of all children, B-ALL with translocation t(9;22)(q34;q11.2) is found. In both children and adults, this type of ALL exhibits the worst prognosis of all ALL entities. The analysis of the BCR-ABL1 fusion transcript by qRT-PCR plays a major role in monitoring therapy and is currently considered the most sensitive method. Detection of the BCR-ABL1 fusion transcript furthermore indicates treatment with imatinib or other tyrosine-kinase inhibitors. Mutations in the ABL1 part of the BCR-ABL1 fusion gene which are acquired in the course of the disease may, however, lead to resistance to imatinib. They can be detected by DNA sequence analysis of the ABL1 gene (see CML).

B-ALL with translocation t(v;11q23) is the most frequently occurring form of leukemia in infants under 1 year of age. However, it is also observed in older children and adults. The region 11q23 contains the MLL gene, which fuses with various translocation partners (e.g. AF4 on chromosome 4q21, ENL on 19p13 or AF9 on 9p22). Especially t(4;11) has an unfavorable prognosis. These leukemias are often associated with overexpression of FLT3.

B-ALL with translocation t(12;21)(p13;q22) is found in approx. 25% of all children suffering from ALL and is rare in adults. It has been associated with a favorable prognosis. The ETV6-RUNX1 fusion transcript that has formed in the process can also be detected by qRT-PCR.

B-ALL with hyperdiploidy is found in approx. 25% of all children suffering from ALL and is rare in adults. It is characterized by a gain of chromosomes (primarily 21, X, 14 and 4) without structural abnormalities and is generally associated with a favorable prognosis.

B-ALL with hypodiploidy is found in approx. 5% of all ALL cases. All patients exhibit a loss of one or several chromosomes. In addition, structural abnormalities may occur. Hypodiploid B-ALL has generally an unfavorable prognosis; the course of the disease, however, has been associated with the number of chromosomes. While B-ALL with 44-45 chromosomes has the most favorable prognosis, B-ALL with an almost haploid set of chromosomes is associated with the poorest prognosis.

B-ALL with translocation t(5;14)(q31;q32) is found in <1% of all cases with ALL.

B-ALL with translocation t(1;19)(q23;p13.3) and the E2A-PBX fusion gene occurs in approx. 6% of all children with ALL and is slightly rarer in adults. It can be treated very well with modern and intensive therapy.

In approx. 50-70% of all T-ALL cases an abnormal karyotype is found. This especially affects translocations in the region 14q11.2, 7q35 and 7p14-15, which can be detected by molecular genetic diagnostics. Furthermore a cryptic interstitial deletion in the chromosomal region 1p32 can lead to a SIL-TAL1 fusion gene. In 50-60% of patients mutations in the NOTCH1 and FBXW7 gene are found which are described as prognostically favorable. Mutations in the DNMT3A, IDH1 and IDH2 gene are mainly found in early immature T-ALL of adult patients and are associated with an unfavorable prognosis. Approximately 15% of patients show mutations in the RUNX1 gene which are associated with an unfavorable prognosis as well. Especially in men with T-ALL additional mutations in PHF6 can be detected.