Prognostification of ALL by Cytogenetics

Abstract

Cytogenetic abnormalities in chromosomal number and structure are common in pediatric ALL and some have prognostic significance. One interesting association between cytogenetic status and treatment response involves the metabolism of methotrexate. Hyperdiploid lymphoblasts accumulate increased amounts of MTX and MTX polyglutamates, and they have higher basal apoptotic rates compared with leukemic cells with lower ploidy and normal cells. These characteristics may contribute to the better outcomes observed for patients with hyperdiploid lymphoblasts. A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51-65 chromosomes) and the ETV6-RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome [t(9;22)], rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).

Flow cytometric predictive scoring systems for common fusions ETV6/RUNX1, BCR/ABL1, TCF3/PBX1 and rearrangements of the KMT2A gene, proposed for the initial cytogenetic approach in cases of B‐acute lymphoblastic leukemia

“…A number of recurrent chromosomal abnormalities have been shown to have prognostic significance in B‐ALL . Identification of prognostic factors is important for stratifying B‐ALL patients into risk groups and tailoring treatment accordingly .…”

“…As in most hematological malignancies, cytogenetic aberrations are recognized to be an important determinant of the biological and clinical features in acute lymphoblastic leukemia (ALL) . In the classification scheme proposed by the World Health Organization (WHO), certain reciprocal chromosomal translocations, namely t(12;21)(p13;q22), t(9;22)(q34;q11), and translocations involving the 11q23 region, t(1;19)(q23;p13), and t(5;14)(q31;q32), are considered sufficient criteria for the definition of distinct disease entities .…”

Trisomy 5 as the sole chromosomal anomaly in acute lymphoblastic leukaemia

“…For example, high hyperdiploidy is associated with improved relapse-free and overall survival, while complex karyotypes, low hypodiploidy and near haploidy are considered adverse prognostic factors 5 6. Some studies have shown that hyperdiploid lymphoblasts accumulate increased amounts of methotrexate and have a higher basal apoptotic rate, which could contribute to the improved outcomes of these patients 7. Cytogenetic analysis impacts treatment choice, with chromosomal abnormalities and their resultant molecular gene products now being used as targets for therapy 8…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…RUNX1, previously known as AML1, located at chromosome 21q22, encodes a transcription factor protein that is important for embryonic hematopoiesis as well as B-cell differentiation in adult blood cell progenitors. Chromosomal translocation t(12;21)(p13;q22) leads to the ETV6-RUNX1 fusion protein, consisting of the N-terminal non-DNA-binding domain of ETV6 combined with RUNX1, and is the most common alteration in childhood B-ALL (∼30%), but it is rarely observed in T-ALL (69). Children with B-ALL correlated with ETV6-RUNX1 show a highly good response to treatment (31).…”