Molecular Biology of Acute Lymphoblastic Leukemia: Implications for Detection of Minimal Residual Disease

Abstract

Acute lymphoblastic leukemias (ALL) are characterized by high frequencies of clonal chromosome aberrations (ploidy aberrations and translocations) as well as by clonal rearrangements of immunoglobulin (Ig) and T-cell receptor (TcR) genes. These two types of clonal molecular characteristics can be used as leukemia-specific markers for detection of minimal residual disease (MRD) by use of polymerase chain reaction (PCR) technology.In case of chromosome aberrations, this concerns translocations which result in fusion genes and fusion transcripts, such as in t(9;22), t(1;19), and t(4;11) in precursor B-ALL, or aberrations with site-specific breakpoints such as tal-1 deletions in T-ALL. In fact, any precisely identifiable breakpoint fusion region of a chromosome aberration can be used as PCR target for MRD detection during follow-up of leukemia patients. So far such breakpoint fusion regions can be identified in 15–20% of childhood ALL and 25–30% of adult ALL.Junctional regions of rearranged Ig and TcR genes represent the second type of MRD-PCR target, which can be precisely identified in ∽80% of precursor B-ALL and in >90% of T-ALL. This especially concerns the junctional regions of rearranged Ig heavy chain (IgH), TcR-γ, and TcR-δgenes. In contrast to chromosome aberrations, the junctional regions of Ig and TcR genes might not remain stable during the disease course, because of continuing rearrangement processes and subsequent subclone formation. These continuing rearrangements are extensive in IgH genes, resulting in the presence of subclones in 30–40% of precursor B-ALL at diagnosis and changes in rearrangement patterns at relapse in 40% of the cases. Continuing rearrangement processes also cause changes in TcR-γ and TcR-δ gene rearrangement patterns at relapse in 10–20% of T-ALL and 35–45% of precursor B-ALL. This heterogeneity in Ig/TcR gene rearrangement patterns at diagnosis and relapse might hamper PCR-mediated MRD detection. However in 75–90% of ALL cases, at least one IgH, TcR-γ, or TcR-δ allele remains stable at relapse. Therefore, two or more junctional regions of different Ig/TcR genes should be monitored for optimal MRD detection during follow-up of ALL patients.Well-designed prospective studies on large series of ALL patients have to demonstrate the clinical impact of MRD detection.KeywordsAcute Lymphoblastic LeukemiaMinimal Residual DiseaseChromosome AberrationJunctional RegionChildhood Acute Lymphoblastic LeukemiaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.