Chromosomal translocation in ALL could be separated into two types, i.e., dysregulation type and chimeric fusion type (Table 15.5) [52–57]. The former group represents involvements of immunoglobulin genes or T-cell receptor genes. Approximately 25 % of T-ALL patients show involvement of T-cell receptor (TCR) genes, i.e., TCRδ (14q11), TCRβ (7q32-36), and altered transcriptional level of involving genes, including c-MYC (located at 8q24), LOM1 (11p15), LOM2 (11q13), HOX11 (10q24), TAL1/SCL (1p32).

The correlation of cytogenetic changes with morphology in AML leads to the identification and characterization of specific disease-associated chromosome abnormalities, while the correlation between morphology and cytogenetic change is not striking in ALL, except for the 8q24 (c-MYC) and ALL-L3 by the FAB classification. In ALL-M3 or Burkitt lymphoma, translocations invariably involve chromosome 8q24 and one of the three chromosomes that carry the immunoglobulin light (2p12: λ-light chain gene and 22q11: k-light chain gene) or heavy chain genes (14q32: heavy-chain gene). These translocations rearrange one allele of c-MYC proto-oncogene at 8q24, which encodes a transcription factor consisting of a basic region helix–loop–helix zipper (bHLH) motif, into the immunoglobulin locus carried on one of these chromosomes, resulting in dysregulation of c-MYC expression through the strong enhancer of immunoglobulin genes [55, 56].

T-cell leukemias (T-ALLs) have a number of different recurring translocations. Most of these involve putative transcription factors, and are not normally expressed in T-cells. As example of this is the HOX11 gene, located on chromosome 10q24, which is activated by translocations t(10;14)(q24;q11) and t(7;10)(q35;q24) in T-ALL. The HOX11 gene shares homology with other homeobox-containing genes that normally code for sequence-specific DNA-binding proteins [57]. The t(1;14)(p32;q11) chromosome translocation has been observed in 3 % of T-ALL patients. This translocation results in the juxtaposition of the SCL gene (also called TAL1) from chromosome 1q32 with the TCRα/δ chain locus on chromosome 14q11 [58]. The SCL gene encodes DNA-binding protein containing the bHLH motif, which can dimerize with protein E47. The chromosomal translocation probably causes ectopic SCL protein expression, activating specific target genes that are transcriptionally silent in normal T cells.

Another chromosomal translocation type in ALL is chimeric protein formation, for example t(1;19) and t(9;22). The t(1;19)(q23;q13) chromosome translocation affects approximately 25 % of pre-B ALLs, and fuses the N-terminal part of the transcription factor E2A, carrying a transcription domain, to the DNA-binding homeodomain of the transcription factor PBX, replacing the bHLH region of E2A [59, 60]. The E2A PBX fusion protein is recognized by the homeodomain of PBX and can strongly activate transcription, whereas PBX cannot. Target genes that bind the PBXC homeodomain in the E2A/PBX fusion protein may be activated and initiate leukemogenesis.

Translocation (12;21)(p13;q22) is found in 20–30 % of childhood ALL, in contrast to 3–4 % in adult ALL, with favorable prognosis. The translocation results in TEL (ETV6)-AML1 (CBF2) fusion and consists of the dimerization domain (HLH) of the TEL gene and the most part of the AML1 protein [61], thus suggesting that homodimer of the TEL-AML1 or heterodimer suppresses the normal TEL function due to a dominant negative effect.

Chromosomal aberrations involving 11q23 is found in 60 % of infantile leukemia (the so-called MLL acute leukemia), possibly due to trans-placental chemical exposure [62]. This anomaly is also characterized by (1) acute leukemia with both lymphoid and myeloid phenotypes, and (2) frequently found in therapy-related adult acute leukemia related with topoisomerase II-inhibitor [63]. The MLL gene is translocated to more than 30 gene loci, and frequent involvements in adult acute leukemia are t(9;11)(p22;q23), following t(6;11)(q27;q23), t(10;11)(p12;q23), t(11;19)(q23;p13) (Table 15.6) [64]. The MLL gene is believed to act to maintain transcription, and the breakpoints of MLL gene in 11q23-leukemia are clustered within 8.5-kb spanned exon 5 to exon 11. The 11q23 translocation creates chimera between the 5′-side of the MLL region including AT-hook and targeted genes, and loss of the zinc finger domain of the MLL gene might be important in the generation of this type of leukemia [65].

The detection of Ph translocation in ALL is diagnostically and therapeutically important. Ph translocation is also detectable in 30 % of adult ALL. This translocation creates the BCR-ABL oncoprotein; some of which have 210KD^BCR-ABL (fusion between ABL and major BCR) which is the transcript similar to those of Ph-positive CML and most patients have 185KD^BCR-ABL (fusion between ABL and minor-BCR). Ph-positive ALL patients have poor prognosis. However, current molecular target therapy, including imatinib or dual SRC-kinase inhibitor, dasatinib, followed by allogeneic stem cell transplantation has yielded promising data for the possibility of obtaining complete remission and maintaining prolonged survival [66, 67], therefore detection of Ph translocation at the ALL diagnosis and incorporation of target therapy is essential in treating such ALL patients.

B-cell malignant lymphomas have translocation involving chromosome 14q32, which contains the immunoglobulin heavy (IgH) chain gene. Two specific translocations involving this locus have been characterized. The chromosomal rearrangements occur at precise locations on chromosomes 11 and 18 at the BCLl and BCL2 loci, respectively. The BCL1 gene, which is aberrantly expressed as a consequence of the t(11;14)(q13;q32) encodes cyclinD1 notable in mantle cell lymphoma (MCL). Cyclin D1 forms a complex with a cyclin-dependent kinase (cdk), and function in cell-cycle regulation [68, 69]. The BCL2 gene is consistently associated with t(14;18) chromosomal translocation observed in a large percentage of B-cell follicular lymphomas. The BCL2 gene product is suggested to mediate inhibition of cellular apoptosis [70, 71]. Thus, constitutive activation of the BCL2 gene may contribute to the formation of follicular lymphoma by blocking programmed cell death.

Anaplastic large cell lymphoma (ALCL) is a variant of non-Hodgkin’s lymphomas composed of large pleomorphic cells that usually express the CD30 antigen and is characterized by frequent cutaneous and extranodal involvement. This type of lymphoma frequently exhibits the t(2;5)(p23;q35) chromosomal translocation that fuses the NPM gene (nucleophosmin) on the 5q35 region to the ALK (anaplastic lymphoma kinase) on the 2p23 chromosomal region [72, 73]. The ALK/NPM fusion protein has tyrosine kinase activity and induces tumorigenesis. ALCL patients with the ALK/NPM fusion protein have favorable prognosis compared to those without the fusion protein, thus indicating the presence of a prognostic factor in ALCL patients.

Trisomy 12 in chronic lymphoid leukemia (CLL) is well known. The t(14;19)(q32;q13.1) chromosomal translocation is noted in some B-CLL. This result in divergent orientation (head-to-head) of the immunoglobulin heavy-chain gene (14q32) and BCL3 (19q13) [74–76]. The BCL3 gene is a distinct member of the IkB family, may function as a positive regulator to NF-kB activity. Thus, overexpression of BCL3 gene by the translocation may alter the transcriptional activity of NF-kB.

Conventional metaphase cytogenetic studies are successful in only 40 % of multiple myeloma (MM) patients studied, due to a slowly proliferation of mature B cells. Using metaphase cytogenetics, only one-third of patients show an abnormal karyotype and the remaining two-thirds have normal metaphase cytogenetics. However, current studies utilizing FISH demonstrated that the large majority of such patients have an aneuploid DNA content and abnormal cytogenetics and impact on prognosis. Well known abnormalities in MM are (1) hyperdiploid (≥48 chromosomes), (2) chromosome 13 deletion, (3) an involvement of 14q32 (IgH) region, i.e., t(11;14)(q13;q32), t(4;14)(p13;q32), and t(14;16)(q32;q23) [77, 78]. Rare translocations t(6;14) and t(14;20) are also notable. Hyperdiploid MM is associated with improved prognosis, and negative prognostic effector in this group is the concomitant presence of high-risk immunoglobulin heavy chain (IgH) translocation. Chromosome 13 deletion is detectable in approximately 50 % of MM patients with abnormal karyotypes (10–20 % of all MM patients), and associated with shorter survival and lower response rate to treatment. The t(11;14) is associated with oligo-secretary or light-chain-only MM, CD20 expression, and amyloidosis (50 %) and IgM MM (>90 %) [77]. The t(11;14)-MM patients show improved or neutral survivals when treated with high-dose chemotherapy and stem cell transplantation. Translocation (4;14) is found in 15 % of MM patients and this translocation results in FGFR3 to the IgH switch region locus. Recently, t(14;16), del(17p), and t(4;14) are known to be linked to poor prognosis after conventional therapy, and thereby it is recommended to utilize fluorescent in situ hybridization to detect these genetic changes, in combination with standard metaphase cytogenetics [79].

Sarcomas are soft tissue tumors that often have chromosomal rearrangements encoding tumor-specific fusion oncoproteins (Table 15.7). Ewing tumors , a subset of sarcomas, occur predominantly in the long bones of children and young adults. Extraskeletal Ewing sarcomas typically involve the soft tissues of the chest wall, paravertebral region, retroperitoneum, and lower extremities. The histogenetic origin of these tumors is now suspected to be neural, a discovery linking Ewing’s sarcoma to more differentiated tumors, known as peripheral primitive neuroectodermal tumors (PNET) or neuroepitheliomas [80]. Approximately 80 % of Ewing family tumors exhibit a balanced chromosomal translocation between chromosome 11 and 22, t(11;22)(q24;q12). Molecular analysis revealed that the chromosome 22 breakpoint present in Ewing tumors is located within the EWS gene, while the chromosome 11 breakpoint is located within the Fli1 gene [81, 82]. Reciprocal translocation between these two chromosomes creates a new chimeric protein combining portions of the EWS and Fli1 proteins. The EWS gene, located on 22q12, plays a recurrent role in several chromosomal translocations found in soft tissue and bone tumors. This gene is involved in all of the alternative translocations identified in Ewing sarcoma/PNET and in distinct translocations found in desmoplastic small round cell tumors, clear cell sarcomas (soft tissue melanomas), cases of extraskeletal myxoid chondrosarcoma, a subset of angiomatoid fibrous histiocytomas, and rarely in myxoid liposarcomas [83, 84]. The EWS and related TLS/FUS/FUS gene products have features typical of RNA-binding proteins; their C-termini, which are deleted from fusion oncoproteins, contain R-G-G repeats flanking a highly conserved RNA-binding domain of the RRM type [85, 86]. The FLI1 gene encodes a DNA-binding protein, Fli1 [85], that appears to function as a transcription factor [81]. The human Fli1 protein shares approximately 70 % sequence identity with the protein encoded by the ETS1 gene. The EWS-Fli1 fusion protein contains the N-terminal domain of EWS and the DNA-binding domain of Fli1. Evidence suggests that DNA-binding activity and subsequent transcriptional activation of various target genes by the EWS-Fli1 fusion are essential for tumorigenesis of Ewing sarcoma [87]. While other chimeric partners of the EWS gene, such as ERG [88], ETV1 [90], ETV4 and E1AF [91], are involved as fusion partners less commonly than FLI1, and all share homology with ETS1.