Transcription factors, translocations, and leukemia

Abstract

The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell development, have been implicated in gene arrangements involving TCR genes and in the SIL/SCL rearrangement, which involves two genes not normally rearranged. However, other mechanisms must clearly be active in generating these molecular abnormalities and perhaps they relate to the multistep maturation and differentiation processes and continuous cell turnover seen in hematopoietic cells. The difficulties in obtaining human solid tumor samples may make it more difficult to identify translocations involving TF genes in solid tumors. Recently, the cytogenetic analysis of solid tumors has improved and specific cytogenetic abnormalities have been associated with specific types of tumors. With advanced techniques, such as fluorescent in situ hybridization (a technique that does not depend on cell growth) and PCR, abnormalities involving TF genes will be discovered. Abnormalities of TF genes, other than translocations, have been seen in a broad variety of nonhematopoietic malignancies. The p53 protein has been shown to bind DNA in a sequence- specific fashion and interact with a variety of DNA tumor virus oncoproteins. The broad range of cell types that harbor p53 abnormalities suggests that TF abnormalities will likely be implicated in many solid tumors. We have detailed several examples of how gene rearrangements that accompany chromosomal translocations in acute leukemia can alter the expression or activity of cellular TFs. Several translocations generate fusion RNA transcripts and fusion TF proteins with altered functional characteristics. Other translocations result in the expression of a gene not normally detectable in hematopoietic cells or alter the level of its expression, or affect the promoter usage or exon structure of the gene (Table 2). Studies are underway in many laboratories to characterize the biologic activity of these abnormal TFs and it remains to be proven that these molecular abnormalities are directly linked with leukemogenesis. The identification of abnormal fusion transcripts and proteins may allow specific therapies to be directed against “tumor-specific” DNA, mRNA, or protein targets. Therapeutic strategies based on antisense or ribozyme technology may be used to turn off expression of these genes and inhibit leukemia cell growth. Immunologic methods can also be used to direct therapy against the malignant cells.

Simultaneous SIL‐TAL1 RT‐PCR detection of all tald deletions and identification of novel tald variants

“…As this number increases, genomic screening for tal d becomes increasingly untenable. The identification of prognostically important fusion transcripts (BCR-ABL, TEL-AML1, E2A-PBX1 and MLL-AF4) in approximately 30% of B-lineage ALL (Nichols & Nimer, 1992;Romana et al, 1995) has led to increasing use of routine diagnostic RT-PCR screening. SIL-TAL1 RT-PCR is probably preferable to genomic tal d DNA analysis for screening T-ALL cases.…”

Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia.

“…Molecular characterization of these abnormalities, especially reciprocal translocations, has shown that the chromosomal abnormalities themselves are implicated in leukemogenesis by altering the function or activities of genes located at or near the translocation breakpoint (Solomon et al, 1991). The inappropriate expression of transcription factors or the creation of fusion mRNAs and fusion transcription factor proteins by chromosomal translocation are important mechanisms in leukemogenesis (Nichols and Nimer, 1992). It is well known that the t(15; 17) in acute promyelocytic leukemia (M3 504 according to the French -American -British classification) (de The et al, 1991;Kakizuka et al, 1991), t(8;21) in acute myelocytic leukemia with maturation (M2) (Miyoshi et al, 1991(Miyoshi et al, , 1993Nucifora et al, 1993), t(6;9) in acute myelocytic or myelomonocytic leukemia (M2 or M4) (von Lindern et al, 1992), and t(l; 19) in acute lymphocytic leukemia (pre-B cell type) (Kamps et al, 1990;Nourse et al, 1990) result in the formation of chimeric transcription factor genes, PML-RARct, AML1-MTG8 or AMLI-ETO, DEK-CAN and E2A -PBXJ, respectively.…”

Heterogeneity of t(1;19)(q23;p13) acute leukaemias

“…Several cases of t(1;19)+, E2A-PBX1 fusion transcript negative B-lineage ALLs have been identified but the breakpoints involved in these cases have not yet been reported, apart from one case with E2A and PBXl variant breakpoints 3' to their 'classic' counterparts (Numata et al, 1993). The E2A gene on chromosome 1 9~1 3 belongs to the helix-loop-helix (Visvader et al, 1991) family of transcription factors (Nichols & Nimer, 1992). A second member of this family, LYL1, also localizes to 1 9~1 3 (30) and was initially identified in a T-ALL demonstrating a t(7;19)(q35;p13) involving the TCR / 3 locus (Mellentin et al, 1989b).…”