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Forced expression of a lineage-restricted regulator

Proliferation genes

Malignancy

Figure 3 Schema of a possible translocation in a pro-B cell. The translocation juxtaposes a powerful transcriptional regulator (TR), not otherwise expressed in this cell lineage, and an immune gene that is normally active in this cell lineage. As a result of the translocation the TR gains a powerful enhancer from the immune locus and is no longer subjected to lineage restriction. The out-of-lineage expression of the transcriptional regulator provides the switch to turn on other target genes initiating a cascade of events that leads to immortalization of this cell and eventually to neoplasia.

directly influence cell cycling and proliferation; 4) genes that affect cell survival.

Translocations that deregulate transcription factors

Among the various lesions that are a hallmark of oncogenic events, deregulation of those genes that themselves coordinate the expression of other genes are by far the most common of all lesions.

Transcription factors are versatile proteins that are essentially DNA-binding proteins. A common feature of these proteins is their modular structure which allows two unique domains to be independently defined, the DNA-binding domain and the transcriptional activation domain (Figure 3). The DNA-binding domain allows these proteins to specifically bind regulatory elements, through which they modulate gene transcription. Several classes of transcription factors have been identified as partners in translocations involving immune genes, these include the basic helix-loop-helix (bHLH) proteins, exemplified by SCL; proteins that contain zinc fingers (e.g. BCL-6), proteins with a cysteine-rich LIM domain like the rhombotin proteins (which also include a zinc finger-like structure), and proteins with specific leucine repeats termed as a leucine zipper, a domain that is found in the c-MYC protein; the c-MYC protein also contains a bHLH motif.

In translocations that involve immune genes and a transcription factor, the expression of these master regulators is deregulated. Since these genes themselves may control the expression of a set of genes that determine cell differentiation and proliferation, it is not surprising that such genetic lesions are oncogenic (Figure 3). In those translocations where the transcription factors are not juxtaposed to immune receptor genes, the deregulation of the transcription factor is often achieved by the formation of novel hybrid proteins where there is an exchange, for example, of the DNA binding domain conferring upon the hybrid protein an altered specificity of transcriptional regulation.

There appears to be a remarkable correlation between the specific type of transcription factor involved in the translocation and the progenitor cell lineage in which it occurs, suggesting strongly that these lesions disrupt regulatory cascades that control cellular differentiation programs. Thus, translocations involving TCRfi and LYL-1 are confined to pro-T ALL while those involving HOX-11 are often seen in pre-T ALL.

In several cases these rearrangements have been directly correlated to mistakes in VDJ recombination. The 'smoking gun' for such mistakes include the presence of nucleotides inserted at the breakpoint junction and the identification of target heptamer-

like sequences in the breakpoint region. Thus, recom-binase errors have been demonstrated in translocations involving HOX-11 and SCL. One of the most common rearrangement involving SCL (lp interstitial deletions) occurs in as much as a quarter of all pediatric T-ALL and although it does not involve the immune genes, it is nonetheless presumed to be mediated by recombinases. This presumption is again based upon sequencing data that demonstrate the presence of extra nucleotides at the breakpoint junctions. The regions of chromosome 1 that are 'stitched' together also harbor heptamer-like recognition sequences, which catalyze erroneous recombination processes.

Translocations that induce an aberrant signal transduction pathway When the extracellular environment is conducive to proliferation, the cell orchestrates various sets of events that result in growth. This communication from the cell surface, which senses the environment through specific receptors, to the nucleus is transduced by pathways specific for a given signal(s). If the molecular switches within these pathways are locked in the 'on' position, the cell will play out all the downstream events and proliferate even in the absence of a signal.

Translocations that involve the immune genes and thereby dysregulate the signal transduction mechanisms include the t(7;9) (q34;q34) present in about 5% of T-ALL and resulting in a rearrangement of the [email protected] locus with TAN-1, and the less frequent t(l;7) (p34;q34) which juxtaposes the LCK gene to the TCR|3 locus. The LCK gene product, which is a receptor tyrosine kinase homologous to the SRC protein, is predominantly expressed in lymphoid cells. TAN-1 is homologous to the Drosophila 'notch' protein which is thought to affect development and cellular differentiation. Unlike LCK, however, the expression of TAN-1 is not preferentially lymphoid. In addition to relocating TAN-1 under the transcriptional control of TCRp, this translocation results in decapitation of the gene, such that the 5' portion of TAN-1 is lost, permitting the redistribution of the protein from its normal location in the plasma membrane to the nucleus.

Translocations that cause a constitutively 'on' cell cycle switch The commitment to enter the cell cycle is an active process initiated by signals received from the extracellular environment. The cell can develop lesions within the cell cycle commitment program, such that it is induced to proliferate even in the absence of upstream signals. A critical phase of the cell cycle commitment occurs in G,. Following commitment to cycle, several proteins are expressed early in the G, phase. These include c-MYC, c-MYB, c-FOS, c-JUN and PCNA. The critical role these proteins play is highlighted by the observations that when expressed inappropriately, a large number of them promote cell transformation. Deregulation of the proto-oncogene c-myc by juxtaposition to an immune gene is seen in both B and T cell lymphomas. In B cell lymphomas, typically in Burkitt's lymphoma, this deregulation in most cases results from transposition of one allele of c-myc - normally present on chromosome 8 - into the Ig heavy-chain locus on chromosome 14. Breakpoint locations vary with respect to geography, thus endemic Burkitt's lymphomas very frequently have breakpoints far upstream of the c-myc gene, whereas sporadic Burkitt's tumors often carry breakpoints within the transcriptional unit of c-myc. It is possible that these breakpoints may be influenced by other factors like the presence of the Epstein-Barr virus, which in certain circumstances may actually influence error-prone recombinations involving the immune genes. Less frequently, the light-chain genes on chromosomes 2 and 22 are involved in deregulation of the expression of c-myc in B cell lymphomagenesis. In these cases the light chain genes are juxtaposed to a site downstream of the c-myc gene. In T cell lymphomas the deregulation of c-myc is achieved by juxtaposition with TCRa.

Among the several proteins that act in concert in allowing the normal progression of the cell cycle, the cyclins play a critical role. Cyclins are expressed transiently during specific phases in the cell cycle and then degraded. Key cyclins mediating Gi transition are cyclins Dl, D2, D3 and E. One error during DJ rearrangement may occur in precursor B cells, leading to a t(ll;14) that gives rise to a low-grade B cell lymphoma classified as mantle cell lymphoma. The partner locus on chromosome 11, known as Bcl-1 or PRAD1, has homology to cyclin Dl which associates with CDK-4 and CDK-6. Following activation of the cyclin D/CDK complex, RB is phosphorylated leading to the release of E2F which is now available to transactivate genes like c-myc, c-myb, thymidylate kinase and thymidine synthetase that are essential for the G,-S transition.

Death-defying translocations A reciprocal translocation between chromosomes 14 and 18 was found to occur frequently in follicular lymphomas. Molecular analysis indicated that the heavy-chain J segments were juxtaposed to a novel locus designated Bcl-2. The majority of breakpoints on chromosome 18 cluster in a short span of about 300 nucleotides termed as 'major breakpoint region' (MBR). Subsequently, another less frequent cluster of breakpoints was identified 30 kb from the MBR and was designated as 'minor cluster region' (mcr). The translocation did not compromise the integrity of the open reading frame of the major transcript from the Bcl-2 locus. Detailed sequence analysis of the recombinational sites revealed the presence of extra nucleotides at the junctions of the derivative chromosomes suggesting an error mediated by recombinases. However, the actual recombination in this translocation may be catalyzed by chi-like séquence elements. Thus, the t(14;l 8)(q32;q21 ) may involve homologous recombination and errors in the action of the recombinases.

Functional analyses to elucidate the pathogenic contribution of the Bcl-2 gene provided insights into a fundamentally novel pathway in tumorigenesis. Aggressive uncontrolled proliferation of cells is one aspect of tumorigenesis, and accumulation resulting from a loss of susceptibility to dying is another pathway to neoplasia. Normal architecture is usually maintained within organs from early in embryogen-esis, because all normal cells are subject to homeostasis. An important mechanism that contributes to this regulation is an inherent ability to selectively deplete cells. This ability is derived from the capacity of cells to activate pathways that result in suicide. These pathways are referred to as apoptosis. It is now apparent how the aberrant loss of this program in a cell in multicellular organisms can lead to neoplasia. The involvement of Bcl-2 in overcoming apoptosis suggested that the deregulation of this death-defying gene interfered with normal B cell ontogeny and prevented the otherwise normal loss of B cells due to programmed cell death. It now appears that resistance to death in several normal lymphoid cells relates to overexpression of Bcl-2. Recently, several other proteins with homology to Bcl-2 have been described. Although none of these members have been associated with chromosomal translocations, it is clear that several members of the Bcl-2 family interact with each other in orchestrating the cell death program.

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