Molecular Characterization of Human Hematopoietic Malignancies

Hematopoietic malignancies are frequently associated with chromosomal translocations, inversions and deletions (Rabbits, 1994; Look, 1997; Rowley, 1999; Chaganti et al., 2000). These genetic events may lead to the aberrant expression/activation of a proto-oncogene, to the generation of an oncogenic fusion gene, or to the deletion/inactivation of a tumor suppressor gene. Mutations of oncogenes and tumor suppressor genes have also been implicated in tumorigenesis of the hematopoietic tissue.

Oncogenes
In the case of hematopoietic neoplasms, the activation of proto-oncogenes is often secondary to chromosomal translocations/inversions, which bring these genes into the vicinities of strong promoters/regulatory elements [e.g. immunoglobulin (Ig) or T-cell receptor (TCR) genes loci (Chaganti et al., 1999)]. Chromosomal translocations associated with Burkitt's lymphoma are probably the best example of this type of activation mechanism. Approximately, 90% of Burkitt's lymphomas harbor a t(8;14)(q24;q32) chromosomal translocation which juxtaposes the MYC proto-oncogene and immunoglobulin heavy-chain (IgH) genes (Finger et al, 1986).

Fusion Genes
In this case, the translocation splits the genes on both partner chromosomes and lead to juxtaposition of part of each gene, thus creating an aberrant fusion gene, which encodes a chimeric protein. It should be noted that the genes involved in these fusions frequently encode transcriptional factors, suggesting that deregulation of gene expression plays a key role in hematopoietic neoplasms (Look, 1997; Salomoni et al., 2000). Gene fusions are by far the most frequent genetic abnormalities associated with hematopoetic malignancies. Tables 1 and 2 list the most frequent gene fusions reported in myeloid and lymphoid neoplasms, respectively (Appendix III). The t(15;17)(q22;q12) of acute promyelocytic leukemia (APL) is a prototypical example of this type of oncogenic mechanism. Due to this chromosomal translocation the retinoic acid receptor a (RARa? gene on chromosome 17 is fused to the Promyelocytic Leukemia gene (PML) on chromosome 15, giving rise to a PML-RARa? fusion gene product (Rego et al., 2001).

Tumor Suppressor Genes
Several tumor suppressor genes have been found deleted or mutationally inactivated in hematopoietic malignancies, such as, for instance, the p53 gene in multiple myeloma (Drach et al., 1998). In other cases, tumor suppressor functions are disrupted as a consequence of chromosomal translocation and/or the dominant negative activity of oncogenic fusion proteins (e.g. the PML tumor suppressor in acute promyelocytic leukemia, which is functionally antagonized by the PML-RARa?fusion oncoprotein; Salomoni and Pandolfi 2002).

Selected References
Chaganti, R.S.K., et al. (2000) Recurring chromosomal abnormalities in Non-Hodgkin's lymphoma: biologic and clinical significance. Semin. in Hematol. 37, 396-411.

Drach, J., et al. (1998) Presence of p53 gene deletion in patients with multiple myeloma predicts short survival after conventional-dose chemotherapy. Blood 92, 802-809.

Finger, L.R., et al. (1986) A common mechanism of chromosomal translocation in T- and B-cell neoplasia. Science 234, 982-985.

Look, A.T. (1997) Oncogenic transcription factors in the human acute leukemias. Science 278, 1059-1064.

Rabbitts, T.H. (1994) Chromosomal translocations in human cancer. Nature 372, 143-149.

Rego, E.M., et al. (2001) Analysis of the molecular genetics of acute promyelocytic leukemia in mouse models. Semin. in Hematol. 38, 54-70.

Rowley, J.D. (1999) The role of chromosome translocations in leukemogenesis. Semin. In Hematol. 36, 59-72.

Salomoni, P., et al. (2000) Transcriptional regulation of cellular transformation. Nat. Med. 6, 742-744.

Salomoni, P., et al. (2002) The role of PML in tumor suppression. Cell 108, 165-170.