Interferon and c-ets-1 genes in the translocation (9;11)(p22;q23) in human acute monocytic leukemia

Gene probes for interferons alpha and beta 1 and v-ets were hybridized to metaphase chromosomes from three patients with acute monocytic leukemia who had a chromosomal translocation, t(9;11)(p22;q23). The break in the short arm of chromosome 9 split the interferon genes, and the interferon-beta 1 gene was translocated to chromosome 11. The c-ets-1 gene was translocated from chromosome 11 to the short arm of chromosome 9 adjacent to the interferon genes. No DNA rearrangement was observed when these probes were hybridized to genomic DNA from leukemic cells of two of the patients. The results suggest that the juxtaposition of the interferon and c-ets-1 genes may be involved in the pathogenesis of human monocytic leukemia.     

Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders

By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.     

Amplification and rearrangement of Hu-ets-1 in leukemia and lymphoma with involvement of 11q23

The Hu-ets-1 oncogene was found to be rearranged and amplified 30-fold in one case of acute myelomonocytic leukemia in which a homogeneously staining region occurred on 11q23; the oncogene was rearranged and amplified approximately tenfold in a case of small lymphocytic cell lymphoma with an inverted insertion that also involved band 11q23. This work suggests that Hu-ets-1 is an unusual oncogene that can help explain the common involvement of chromosome band 11q23 in various subtypes of hematopoietic malignancies.     

The role of the c-mos gene in the 8;21 translocation in human acute myeloblastic leukemia

The human c-mos proto-oncogene is located on chromosome 8 at band q22, close to the breakpoint in the t(8;21) (q22;q22) chromosome rearrangement. This translocation is associated with acute myeloblastic leukemia, subgroup M2. The c-myc gene, another proto-oncogene, has been mapped to 8q24. The breakpoint at 8q22 separates these genes, as determined by in situ hybridization of c-mos and c-myc probes. The c-mos gene remains on the 8q-chromosome and the c-myc gene is translocated to the 21q+ chromosome. Southern blot analysis of DNA from bone marrow cells of four patients with this translocation showed no rearrangement of c-mos.     

Translocation and rearrangement of myeloperoxidase gene in acute promyelocytic leukemia

Acute promyelocytic leukemia (subtype M3) is characterized by malignant promyelocytes exhibiting an abundance of abnormally large or aberrant primary granules. Myeloperoxidase (MPO) activity of these azurophilic granules, as assessed by cytochemical staining, is unusually intense. In addition, M3 is universally associated with a chromosomal translocation, t(15;17)(q22;q11.2). In this report, the MPO gene was localized to human chromosome 17 (q12-q21), the region of the breakpoint on chromosome 17 in the t(15;17), by somatic cell hybrid analysis and in situ chromosomal hybridization. By means of MPO complementary DNA clones for in situ hybridization and Southern blot analysis, the effect of this specific translocation on the MPO gene was examined. In all cases of M3 examined, MPO is translocated to chromosome 15. Genomic blot analyses indicate rearrangement of MPO in leukemia cells of two of four cases examined. These findings suggest that MPO may be pivotal in the pathogenesis of acute promyelocytic leukemia.     

Modeling the initiation and progression of human acute leukemia in mice

Our understanding of leukemia development and progression has been hampered by the lack of in vivo models in which disease is initiated from primary human hematopoietic cells. We showed that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. The properties of these cells provide a biological basis for several clinical hallmarks of MLL leukemias.     

A common mechanism of chromosomal translocation in T- and B-cell neoplasia

The chromosomal breakpoint involved in the t(8;14)(q24;q11) chromosome translocation in the SKW-3 cell line, which directly involves the 3' flanking region of the c-myc gene, was cloned and sequenced. The breakpoint on chromosome 8 mapped to a position 3 kb 3' of c-myc while the chromosome 14 breakpoint occurred 36 kb 5' of the gene for the constant region of the alpha chain of the T-cell receptor (TCR). The translocation resulted in a precise rearrangement of sequences on chromosome 8 and what appears to be a functional J alpha segment on chromosome 14. Signal sequences for V-J joining occurred at the breakpoint positions on both chromosomes 14 and 8, suggesting that the translocation occurs during TCR gene rearrangement and that it is catalyzed by the enzymatic systems involved in V-J joining reactions. The involvement of c-myc in the translocation and the association of joining signals at the breakpoints provides a parallel to the situation observed in the translocations involving c-myc and the immunoglobulin loci in B-cell neoplasms and suggests that common mechanisms of translocation and oncogene deregulation are involved in B- and T-cell malignancies.     

Locus of the alpha-chain of the T-cell receptor is split by chromosome translocation in T-cell leukemias

Mouse lymphoma cells were hybridized with two human acute T-cell leukemias with a t(11;14) (p13;q11) translocation and the segregated hybrids were examined for the presence of the DNA segments coding for the constant (C) and the variable (V) regions of the alpha chain (C alpha and V alpha) of the T-cell receptor. The C alpha segment was translocated to the involved chromosome 11 (11p+) while the V alpha segment remained on the involved chromosome 14 (14q-). The data indicate that the locus for the alpha chain of the T-cell receptor is split by the chromosomal breakpoint between the V alpha and the C alpha gene segments, and that the V alpha segments are proximal to the C alpha segment within chromosome band 14q11.2.     

Relationship between the c-myb locus and the 6q-chromosomal aberration in leukemias and lymphomas

Deletions of the long arm of chromosome 6 (6q-) are frequently found in hematopoietic neoplasms, including acute lymphoblastic leukemias, non-Hodgkin lymphomas and (less frequently) myeloid leukemias. The c-myb proto-oncogene has been mapped to region 6q21-24, which suggests that it could be involved in the 6q- aberrations. By means of in situ chromosomal hybridization on cells from six hematopoietic malignancies, it was demonstrated that the c-myb locus is not deleted, but is retained on band q22, which is consistently bordered by the chromosomal breakpoints in both interstitial and terminal 6q- deletions. The deletion breakpoints were located at some distance from the myb locus since no rearrangement of c-myb sequences was found. In one case, however, amplification of the entire c-myb locus was detectable. Furthermore, in all cases tested that carry 6q- deletions, myb messenger RNA levels were significantly higher than in normal cells or in malignant cells matched for lineage and stage of differentiation but lacking the 6q- marker. These results indicate that 6q- deletions are accompanied by structural and functional alterations of the c-myb locus and that these alterations may be involved in the pathogenesis of leukemias and lymphomas.     

Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization

Chronic myelogeneous leukemia (CML) is genetically characterized by fusion of the bcr and abl genes on chromosomes 22 and 9, respectively. In most cases, the fusion involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). Fusion can be detected by Southern (DNA) analysis or by in vitro amplification of the messenger RNA from the fusion gene with polymerase chain reaction (PCR). These techniques are sensitive but cannot be applied to single cells. Two-color fluorescence in situ hybridization (FISH) was used with probes from portions of the bcr and abl genes to detect the bcr-abl fusion in individual blood and bone marrow cells from six patients. The fusion event was detected in all samples analyzed, of which three were cytogenetically Ph1-negative. One of the Ph1-negative samples was also PCR-negative. This approach is fast and sensitive, and provides potential for determining the frequency of the abnormality in different cell lineages.     

The human gene encoding GM-CSF is at 5q21-q32, the chromosome region deleted in the 5q- anomaly

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 22,000-dalton glycoprotein that stimulates the growth of myeloid progenitor cells and acts directly on mature neutrophils. A full-length complementary DNA clone encoding human GM-CSF was used as a probe to screen a human genomic library and isolate the gene encoding human GM-CSF. The human GM-CSF gene is approximately 2.5 kilobase pairs in length with at least three intervening sequences. The GM-CSF gene was localized by somatic cell hybrid analysis and in situ hybridization to human chromosome region 5q21-5q32, which is involved in interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. An established, human promyelocytic leukemia cell line, HL60, contains a rearranged, partially deleted GM-CSF allele and a candidate 5q- marker chromosome, indicating that the truncated GM-CSF allele may reside at the rejoining point for the interstitial deletion on the HL60 marker chromosome.     

Development and Identification of Triticum aestivum L.-Thinopyrum bessarabicum L(o)ve Chromosome Translocations

With ass7istance of chromosome C-banding and genomic in situ hybridization(GISH)combined with meiotic analysis,five germplasms with homozygous wheat-Th. Bessarabicum chromosome translocations were developed and identified among BC1F5 progenies of the cross between T. Aestivum cv. Chinese Spring and Chinese Spring-Th. Bessarabicum amphiploid. These lines included Tj01 and Tj02(2n=44)containing a pair of wheat-Th. Bessarabicum translocation chromosomes besides a pair of added Th. Bessarabicum chromosomes,Tj03(2n=44)with a pair of added interspecific translocation chromosomes,Tj04(2n=44)containing a pair of interspecific translocation chromosomes besides an added pair of Th. Bessarabicum chromosome arms and Tj05(2n=46)containing a pair of interspecific translocation chromosomes besides two pairs of added intact alien chromosomes. The breakpoints of all the translocations were found to be not around centromere. Meanwhile,all the lines showed normal plant growth,development and fertility,while the translocation chromosomes transmitted regularly. The obtained translocations might be of use for transferring elite genes from Th. Bessarabicum into wheat.     

Chromosomal localization of the human homolog (c-sis) of the simian sarcoma virus onc gene

Nonrandom chromosome rearrangements of chromosome 22 have been identified in different human malignancies. As a result of Southern blot hybridization of a c-sis probe to DNA's from mouse-human somatic cell hybrids, the human homolog (c-sis) of the transforming gene of simian sarcoma virus was assigned to chromosome 22. Hybrids between thymidine kinase-deficient mouse cells and human fibroblasts carrying a translocation of the region q11-qter of chromosome 22 to chromosome 17 were also analyzed. These studies demonstrate that the human c-sis gene is on region 22q11 greater than qter.     

Gene for alpha-chain of human T-cell receptor: location on chromosome 14 region involved in T-cell neoplasms

A human complementary DNA clone specific for the alpha-chain of the T-cell receptor and a panel of rodent X human somatic cell hybrids were used to map the alpha-chain gene to human chromosome 14 in a region proximal to the immunoglobulin heavy chain locus. Analysis by means of in situ hybridization of human metaphase chromosomes served to further localize the alpha-chain gene to region 14q11q12, which is consistently involved in translocations and inversions detectable in human T-cell leukemias and lymphomas. Thus, the locus for the alpha-chain T-cell receptor may participate in oncogene activation in T-cell tumors.     

Genetic variation affects de novo translocation frequency

Translocation is one of the most frequently occurring human chromosomal aberrations. The constitutional t(11;22)(q23;q11), which is the only known recurrent non-Robertsonian translocation, represents a good model for studying translocations in humans. Here we demonstrate polymorphisms of the palindromic sequence at the t(11;22) breakpoint that affect the frequency of de novo translocations in sperm from normal males. A typical allele consists of a perfect palindrome, producing ~10-5 de novo t(11;22) translocations. Alleles with an asymmetric center do not form the t(11;22). Our data show the importance of genome sequence on chromosomal rearrangements, a class of human mutation that is thought to be random.     

The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining

In this study, the joining sequences between chromosomes 14 and 18 on the 14q+ chromosomes of a patient with pre-B-cell leukemia and four patients with follicular lymphoma carrying a t(14;18) chromosome translocation were analyzed. In each case, the involved segment of chromosome 18 has recombined with the immunoglobulin heavy-chain joining segment (JH) on chromosome 14. The sites of the recombination on chromosome 14 are located close to the 5' end of the involved JH segment, where the diversity (D) regions are rearranged with the JH segments in the production of active heavy-chain genes. As extraneous nucleotides (N regions) were observed at joining sites and specific signal-like sequences were detected on chromosome 18 in close proximity to the breakpoints, it is concluded that the t(14;18) chromosome translocation is the result of a mistake during the process of VDJ joining at the pre-B-cell stage of differentiation. The putative recombinase joins separated DNA segments on two different chromosomes instead of joining separated segments on the same chromosome, causing a t(14;18) chromosome translocation in the involved B cells.