Activation of the abl oncogene and its involvement in chromosomal translocations in human leukemia

Activation of the abl gene and its involvement in human leukemia is one of the most thoroughly characterized examples of the structural alterations of chromosomes associated with the conversion of a normal cell into a cancer cell. The abl oncogene as first identified on the Abelson murine leukemia virus (A-MuLV). Activation of the viral oncogene is associated, in part, with the truncation of the gene at its 5' end. As in studies with other retroviruses, results with A-MuLV presaged the mechanism of activation by abl in naturally occurring human malignancies. Thus, chronic myelogenous leukemia (CML) is consistently associated with a translocation of a piece of chromosome 9 onto chromosome 22 creating what is known as the Philadelphia chromosome (Ph1). The result of this translocation is the truncation of the 5' end of the cellular abl gene, which is located at the breakpoint of chromosome 9. The function of the abl gene product is poorly understood but is thought to participate in an, as yet, undefined pathway of growth control signals, which originate outside the cell, and traverse through the cell into its nucleus. The loss of the gene product's N-terminal amino acid sequences brought about by the truncation of the 5' portion of the gene is consistent with the hypothesis that the protein's growth-controlling activity is deregulated by the structural alterations which occur in the cancer cells. The abl gene and CML serve as a paradigm of the mechanism of activation of proto-oncogenes by chromosomal alterations. The case of CML and the Ph1 chromosome illustrates the findings we might expect as other chromosomal abnormalities are characterized at the molecular level.     

Palindrome-mediated chromosomal translocations in humans

Recently, it has emerged that palindrome-mediated genomic instability contributes to a diverse group of genomic rearrangements including translocations, deletions, and amplifications. One of the best studied examples is the recurrent t(11;22) constitutional translocation in humans that has been well documented to be mediated by palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11. De novo examples of the translocation are detected at a high frequency in sperm samples from normal healthy males, but not in lymphoblasts or fibroblasts. Cloned breakpoint sequences preferentially form a cruciform configuration in vitro. Analysis of the junction fragments implicates frequent double-strand-breaks (DSBs) at the center of both palindromic regions, followed by repair through the non-homologous end joining (NHEJ) pathway. We propose that the PATRR adopts a cruciform structure in male meiotic cells, creating genomic instability that leads to the recurrent translocation.     

The mystery of chromosomal translocations in cancer

Chromosomal translocations in human cancer may result in products that can be suppressed by targeting drugs. An example is bcr-abl tyrosine kinase in chronic myelogenous leukemia that can be treated with imatinib mesylate. However, the mechanisms of translocations or exchanges of chromosomal segments are virtually unknown. In this summary, chromosomal translocations in human cancer are compared with 'crossing over' of chromosomal segments occurring during the first meiotic division. Several proposed mechanisms of the exchange of DNA between and among chromosomes are discussed. The conditions that appear essential for these events to occur are listed. Among them are proximity of the involved DNA segments, mechanisms of excising the target DNA, its transport to the new location, and integration into the pre-existing chromosome. The conclusion based on extensive review of the literature is that practically nothing is known about the mechanism of 'crossing over' or translocation. Based on prior work on normal human cells, it is suggested that only one of the two autosomes participates in these events that may include loss of heterozygozity, another common abnormality in human cancer.     

AID and Igh switch region-Myc chromosomal translocations

Chromosomal translocations involving Ig heavy chain switch regions and an oncogene, like Myc, represent early initiating events in the development of many B cell malignancies. These translocations are widely believed to result from aberrant class switch recombination (CSR). Recent reports have produced conflicting models for the role of activation-induced cytidine deaminase (AID) in this process. Here, we discuss possible roles of AID, CSR, and somatic hypermutation in generating chromosomal translocations and in tumor progression.     

Topoisomerase II and the etiology of chromosomal translocations

Acute leukemias with balanced chromosomal translocations, protean morphologic and immunophenotypic presentations but generally shorter latency and absence of myelodysplasia are recognized as a complication of anti-cancer drugs that behave as topoisomerase II poisons. Translocations affecting the breakpoint cluster region of the MLL gene at chromosome band 11q23 are the most common molecular genetic aberrations in leukemias associated with the topoisomerase II poisons. These agents perturb the cleavage-religation equilibrium of topoisomerase II and increase cleavage complexes. One model suggests that this damages the DNA directly and leads to chromosomal breakage, which may result in untoward DNA recombination in the form of translocations. This review will summarize the evidence for topoisomerase II involvement in the genesis of translocations and extension of the model to acute leukemia in infants characterized by similar MLL translocations.     

Induction and transmission of wheat-Haynaldia villosa chromosomal translocations

In order to develop more wheat-Haynaldia villosa translocations involving different chromosomes and chromosome segments of H. villosa, T. durum-H, villosa amphiploid was irradiated with ^60Co γ-rays at doses of 800, 1,200, and 1,600 rad. Pollen collected from the spikes 1, 2, and 3 days after irradiation were transferred to emasculated spikes of the common wheat cv. ‘Chinese Spring＇. Genomic in situ hybridization was used to identify wheat-H, villosa chromosome translocations in the M1 generation. Transmission of the identified translocation chromosomes was analyzed in the BC1, BC2, and BC3 generations. The results indicated that all three irradiation doses were highly efficient for inducing wheat-alien translocations without affecting the viability of the M1 seeds. Within the range of 800-1,600 rad, both the efficiency of translocation induction and the frequency of interstitial chromosome breakage-fusion increased as the irradiation dosage increased. A higher translocation induction frequency was observed using pollen collected from the spikes 1 day after irradiation over that of 2 or 3 days after irradiation. More than 70% of the translocations detected in the M1 generation were transmitted to the BC1 through the female gametes. All translocations recovered in the BC1 generation were recovered in the following BC2, and BC3 generations. The transmission ability of different translocation types in different genetic backgrounds showed an order of ‘whole-arm translocation 〉 small alien segment translocation 〉 large alien segment translocation＇, through either male or female gametes, In general, the transmission ability through the female gametes was higher than that through the male gametes. By this approach, 14 translocation lines that involved different H. villosa chromosomes have been identified in the BC3 using EST-STS markers, and eight of them were homozygous.     

A family with two different chromosomal translocations

The proband was a 22-year-old woman who had two spontaneous abortions in the first trimester of pregnancy. She had a consanguineous marriage with no history of malformation or developmental disorders in the family. Her gynecological examination was normal. Chromosome analysis of the family showed two different katyotypes 46,XY,t(1;16)(p22;p13) and 46,XX,t(1;16)(q24;q24) using high-resolution banding (HRB). Proband's family was also examined for chromosome analysis. A t(1;16)(p22;p13) was found in the husband's father and other relatives, and a t(1;16)(q24;q24) translocation in the proband's family. This second tanslocation is not found in her parents.     

Segregation of two independent chromosomal translocations in one family

Summary A family with two independent reciprocal translocations t(3;19) and t(16;22) is described. The proband, a 4-week-old male, was phenotypically conspicious with multiple congenital anomalies. Cytogenetic examination revealed a balanced reciprocal translocation (3;19) and a supernumerary small marker chromosome. His mother carried two balanced reciprocal translocations, the one found in the proband and a reciprocal translocation (16;22). The maternal grandmother and a maternal uncle were identified as carriers of a single translocation (16;22). The findings in the family members permitted the identification of the proband's marker chromosome as a derivative chromosome 22 resulting in partial trisomy 16 and 22.     

Variant Philadelphia translocations in chronic myeloid leukemia

Up to the beginning of 1986, some 327 variant Philadelphia translocations were reported in chronic myeloid leukemia. The present study represents an attempt to determine which factors (sex, age, geographic localization, etc.) influence the occurrence and chromosome involvement of these variant Philadelphia (Ph1) translocations. Clinical data indicated that band 9q34 was always rearranged in the variant Ph1 translocations and no difference existed between the hematologic and prognostic features among patients with the standard and the variant translocations. An uneven geographic distribution of the variant Ph1 translocations was found. Whether this was due to populations with different ethnic backgrounds or to environmental factors could not be determined. Twenty-eight bands were shown to be rearranged more frequently than expected (P less than 0.05); 27 of them are known to contain a fragile site and/or an oncogene and/or are rearranged more frequently than expected in other malignancies. The chromosomes involved in these variant Ph1 translocations were found to show a very particular geographic distribution, which cannot be explained at present.     

Breakpoints in variant Philadelphia translocations in chronic myeloid leukemia

To date, 327 cases of variant Philadelphia translocations found in chronic myeloid leukemia have been described. A statistical analysis using the Monte Carlo simulation was performed to determine which chromosomal bands were preferentially involved in variant Philadelphia translocations. The results showed that twenty-eight bands were significantly rearranged (P less than 0.05).     

Chromatin diminution and a chromosomal mechanism of sexual differentiation in Strongyloides papillosus

Eggs obtained from feces of rabbits infected with Strongyloides papillosus were squashed and the karyotypes were determined. They contained cells with either two long and two medium sized chromosomes (2L2M), or one long, three medium and one short chromosome (L3MS). Two types of parasitic female gonad could be distinguished on the basis of oocyte chromosome morphology at prometaphase of the maturation division. All the oocytes in a gonad contained either two upaired long chromosomes and two unpaired medium sized chromosomes, or two unpaired medium sized chromosomes and two unpaired chromosomes segmented into beads in one region. At the maturation division in mitotic parthenogenesis the beads appear to be lost from one of the chromosomes. This generates a medium sized and a shorter chromosome, which together with the undiminished chromosomes make up the L3MS karyotype. Animals with beaded oocyte chromosomes lay eggs that develop into males. It is suggested that males are heteromorphic for the long homologue due to chromatin diminution, that occurs in the maturation division of mitotic parthenogenesis.     

Chromatin and chromosomal fine structure in spermatogenesis of some species of amphibians

Spermatogenesis is a complex differentiation process which is characterised, among other features, by conspicuous stage-specific nuclear events such as the pairing of homologous chromosomes coupled with the formation of synaptonemal complexes, the replacement of histones with sperm-specific proteins during spermiogenesis and, as a result, chromatin condensation and its inactivation in sperm cells. The chromatin of spermatogenic cells undergoes dramatic conformational changes upon differentiation from spermatogonia to mature spermatozoa. During the haploid stage of spermatogenesis, histones are gradually replaced, firstly by transition proteins and later by sperm-specific proteins. As a result of the high degree of condensation and inactivation of spermatid and sperm chromatin, Sertoli cells are responsible for the nourishment of germ cells with ribosomal RNA and nutritive substances.