IG and TCR Gene Rearrangements in ALL

The immune system can specifically recognize and distinguish an enormous variety of specific antigens and anti-genic epitopes (at least 1010). Each lymphocyte has a unique membrane receptor, the immunoglobulin receptor (IG) on B lymphocytes, and the T-cell receptor (TCR) on T lymphocytes, that recognizes specific antigens.

Rearrangements of gene segments that encode the variable regions of the IG and TCR genes are responsible for the enormous diversity of antigen-specific lymphocyte receptors.8-12 This great variability of IG and TCR is mediated by several mechanisms: (1) the number of variable or V, diversity or D, and joining or J segments (germline genome diversity); (2) the number of possible V(-D)-J combinations (combinatory diversity); (3) deletions of nucleotides at the ends of rearranging V, (D), and J gene segments, as well as random insertion of noncoded nucleotides (N-region nucleotides) between V-D and D-J segments (junctional diversity); and (4) somatic mutations in the V gene segments of the IG genes. This last process has not been observed for TCR genes.10'12'13

The V, (D), and J segments of B and T precursor cells are rearranged during their differentiation, and each lymphocyte, in this way, contains a specific combination of V-(D-) and J segments.1014 Additional variability can be generated in the junctions V-D and D-J through the loss of nucleotides, as well as insertion of new nucleotides. Insertion of nucleotides (insertion of N regions) in the junctional sites is mediated by the enzyme terminal deoxynucleotidyl transferase (TdT), which is present in the nucleus of immature B and T cells. N-region insertion occurs in rearranged immunoglobulin heavy chain (IGH) genes, but is limited or absent in the immunoglobulin kappa and lambda light chain genes (IGLK and IGLL). Junctional diversity also occurs in TCR genes,primarily the T-cell receptor delta and gamma genes (TCRD and TCRG). The potential diversity introduced by the addition of N regions is very high and can increase the total combinatorial diversity to more than 1010 for the IGH molecules, 1012 for TCRAB, and more than 109 for TCRDG.10'12

During B-cell differentiation, the IGH genes rearrange before the IGL genes, and of the IGL genes, IGLK is the first to rearrange; if the IGLK rearrangement is not functional, the IGLL gene will rearrange. Another type of rearrangement of the IGH gene that can occur is the process of class switching, from IgM and IgD to IgG, IgA, or IgE.10'12

During the differentiation of T cells, the TCRD gene is the first to rearrange, followed immediately by rearrangement of the TCRG gene and in many cells also the rearrangement of the TCRB gene. The TCRD gene can be deleted when TCRA rearrangement occurs.10'12'15 Since ALL is derived from a single transformed lymphoid precursor cell, all ALL cells of a patient in principle have the same IG and TCR gene rearrangements with identical junctional region sequences that can be regarded as leukemia-specific fingerprints. Such targets can be identified at initial diagnosis in more than 95% of patients with ALL by using various polymerase chain reaction (PCR) primer sets.16-20 Studies of rearrangements of the IG genes in B-lineage ALL by Southern blot and PCR have shown that, despite an immature phenotype, more than 95% of B-precursor ALL

contain IGH rearrangements, approximately 60% have IGLK rearrangements or deletions, and approximately 20% have IGLL rearrangements.12'16'17'19 Cross-lineage rearrangements of the TCR gene also have been observed in approximately 90% of B-lineage ALL pediatric patients.20 Rearrangements of TCRA, TCRB, TCRD, and TCRG are found in 46% to 61%, 29% to 35%, 54% to 80%, and 49% to 70% of B-lineage ALL, respectively.21-26 In B-precursor ALL, approximately 80% of all TCRD rearrangements are due to incomplete gene rearrangements V82-D83 and DS2-DS3.12'15'22 These V82-D83 rearrangements also are prone to continuing rearrangements, particularly with Ja gene segments. V82-Ja rearrangements are detected in approximately 40% of childhood B-precursor ALL and are rare or absent in normal lymphoid cells.27

In T-lineage ALL, TCRA, TCRB, TCRD, and TCRG gene rearrangements have been described in 17% to 67%, 85% to 89%, 68% to 90%, and 90% to 100% of cases, respec-tively.12,19,23,24 Cross-lineage IG gene rearrangements are not very common in T-lineage ALL, occurring in less than 20% of cases, and involving only IGH rearrangements.12 19 23 24

The explanation for these cross-lineage rearrangements of the IG and TCR genes in non-B and non-T cells, respectively, is probably due to the fact that the leukemic cells originate from a less-committed lymphoid precursor or even a more-primitive pluripotential cell (lymphoid/myeloid), where both IG and TCR genes are accessible to a common recombinase enzyme. Such rearrangements occur before the final determination of lineage; as soon as this determination for the B, T, or myeloid lineage occurs, the cell adopts the lineage-specific phenotype with expression or differentiation of the lineage-specific antigen, while the gene of cross lineage persists as an "artifact." Due to this, rearrangements in the TCR gene are relatively common in B-precursor cell ALL; however, they are very rare in B-ALL and mature B-cell neoplasia (B-cell chronic lymphocytic leukemia [B-CLL], multiple myeloma, and B-cell non-

Hodgkin's lymphoma [B-NHL]).19,20 Similarly, rearrangements of IG genes are rare in mature T-cell neoplasms (T-cell chronic lymphocytic Leukemia [T-CLL] and T-cell non-Hodgkin's lymphoma [T-NHL]).19,20

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