The clinical utility of the CDR3 DNA sequence

The description of V-D—J recombination may appear arcane, with no obvious relevance in clinical terms, but it is the formation of this unique recombination product that generates a powerful specific-specific marker that we can use for the detection of malignant clones and MRD. The DNA sequence within the V-D-J is determined by sequencing, following which the individual V, D and J segments are delineated. This allows accurate identification of the N region nucleotides (which are generated randomly by the enzyme TdT) that form the basis of the unique clone-specific (patient-specific) probe (Figure 6.6).

There are two sites available for design of the customized probe—the DNA of the V-N-D sequence and that of the D-N-J sequence. Does it matter which one we use to make the probes? The V-N-D sequence generally has a larger N region with more random nucleotides inserted, but the D-N-J site appears preferable for use as a clone-specific probe since there is less base deletion of the 3' end of the framework region 3 (FR3) than of the 5' end of the J region. In addition, the D-J segments appear to be inherently more stable than V-D segments. Finally, where there is V^V switching, as happens in some diseases, such as ALL, the D-J segment remains unchanged and the probe will still detect the clone even if the V regions alter. The consensus view at present is that the D-N-J is probably the best DNA sequence to use to make probes for MRD detection.

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