Leukemia and lymphoma in ataxia telangiectasia

Abstract

There is a large increase in lymphoid malignancy in A-T patients and a total absence of myeloid tumors. Penetrance of the tumor phenotype is about 10% to 15% by early adulthood. The increase in lymphoid malignancy includes both B- and T-cell tumors. However, young A-T patients do not show an increased susceptibility to cALL, and the UK data suggest that B-cell lymphoma occurs in older A-T children. T-cell tumors may occur at any age and may be T-ALL, T-cell lymphoma, or T-PLL; most strikingly, there may be a fourfold to fivefold increased frequency of T-cell tumors compared with that of B-cell tumors in these patients. If this is correct, it is possible that a significant proportion of all T-ALL/T-cell lymphoma in infants might be associated with undiagnosed A-T. The age range and sex predominance for T-ALL may be different for A-T and non-A-T patients and the age range for T-PLL may also be different in A-T and non-A-T patients. There is clearly some uncertainty concerning the ratio of T-cell to B-cell tumors in A-T, but this could be clarified by the publication of all tumors that occur in the disorder. In contrast, 8 of 9 tumors reported in NBS, which shows the same cellular features as A-T, were lymphomas and none was a leukemia. There are several indicators of genetic heterogeneity in A-T that suggest that not all patients are equally susceptible to all T-cell tumor types. Concordance for tumor type within individual families suggests that particular gene defects may be associated with particular tumor types. The logical extrapolation of this argument is that some patients may not have any increased risk for B-cell tumors at all or even to all T-cell types but only to a particular type of T-cell tumor. What is the cause of the increased predisposition to leukemia/lymphoma in A-T patients? There is no evidence that the immunodeficiency in A-T is related to this predisposition. One of the major findings in all A-T patients is the increase in V(D)J-mediated chromosome rearrangement observed in T lymphocytes. Particular chromosome translocations in T cells, involving a break in a TCR gene, are characteristically associated with either T-ALL or T-PLL in non-A-T patients. The majority of T-cell tumors in A-T are T-ALL and T-cell lymphoma, about which virtually nothing is known chromosomally, and the assumption is that the increased number of translocations leads to the increased level of these tumors. In older T patients, the expansion of specific translocation T-cell clones has been followed to the point to which they develop into T-PLL. All the evidence, therefore, suggests that the A-T mutation in the homozygous state allows a large increase in production of translocations formed at the time of V(D)J recombination, and this leads to the increased predisposition to leukemia. The general increased predisposition to T-cell tumors compared with B-cell tumors in A-T patients may be related to a preferential occurrence of translocations in T cells. Relatively little is known about translocations in circulating B lymphocytes in normal individuals, but A-T siblings have been shown to have clonal chromosome rearrangements of both B and T cells, simultaneously, although in these siblings the T-cell clones occupied all the T-cell compartment and the B-cell clones were small. An important inference from these facts is that the A-T defect preferentially affects immune system gene recombination in T cells rather than B cells. Recent evidence suggests that the V(D)J recombination machinery is not identical or is not regulated identically in T- and B-cell progenitors. This finding is consistent with the hypothesis that V(D)J rejoining in the majority, at least, of A-T patients may be preferentially deficient in T cells compared with B cells giving rise to the greatly increased number of translocations and T-cell tumors. Carbonari et al proposed that the recombination defect in A-T cells affected both Ig isotype switching and TCR rearrangeme

Expression of the TCL1 Gene at 14q32 in B‐Cell Malignancies but Not in Adult T‐Cell Leukemia

“…2,3) A large proportion of patients with T-cell prolymphocytic leukemia (T-PLL) and T-cell leukemia developing from ataxia telangiectasia carry t(14;14)(q11;q32), inv(14)(q11;q32) or t(7;14)(q35;q32), which juxtapose the TCL1 locus to the α/δ or β loci of the T cell receptor (TCR). [4][5][6] This points to the presence of a gene which is activated by the juxtaposition of TCR, as found for MYC or BCL2 translocations with activation by the immunoglobulin gene (Ig) in B-cell malignancies. Virgilio et al 7) recently identified a transcript from the TCL1 locus and designated it as the TCL1 gene, although direct evidence for activation by juxtaposition to TCR genes remains elusive.…”

The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target

“…A gene upstream of TP53 that has been implicated in the predisposition to lymphoid malignancies such as T-prolymphocytic leukaemia (T-PLL) and CLL is the ATM gene, a protein kinase mutated in the genetic instability syndrome called ataxia-telangiectasia (Taylor et al, 1996). Its major function is to maintain genetic stability by activating G1/S, S and G2/M cell cycle checkpoints in response to DNA double-stranded break damage (Shiloh, 2003).…”

Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients

“…Thirdly, myeloma is characteristically associated with chromosome translocations involving the IgH locus at 14q32. Translocations involving breakpoints in immune system genes are seen at a much higher rate in lymphocytes of A-T patients, defective in ATM, compared with normal and indeed, progenitors carrying such translocations have been shown to give rise to T-cell prolymphocytic leukaemia in these patients (Taylor et al, 1996). Interestingly, the ATM R3047X mutation was observed in a patient with T-cell prolymphocytic leukaemia and concomitant IgA myeloma, carrying a t(14;14)(q11;q32) translocation (Zech et al, 1983;Vorechovsky et al, 1997).…”