A novel chromosomal abnormality t (9;14)(p24;q13) in B-acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. We describe the clinical, morphologic, immunophenotypic and cytogenetic findings in the case of a 26-year-old man with B-lymphoblastic leukemia. Surface marker analysis revealed that they are positive for CD markers CD10, CD19, CD13, CD34, CD45 and HLA-DR, but negative for CD20, CD33, CD117 and CD11C markers. Cytogenetic analysis established a novel translocation, t (9;14)(p24;q13). Apart from this, spectral karyotyping revealed an additional translocation, t (6p; 14q). This is the first documented case of B-lymphoblastic leukemia with concurrent occurrence of both abnormalities. Further studies are needed to understand the role of this abnormality in carcinogenesis.     

LMO2与T细胞白血病

Lmo2基因是LMO(LIM-only)家族的成员之一。作为一个原癌基因,Lmo2的染色体异位t(11;14)(p13;q11)或t(7;11)(q35;p13)与T细胞急性淋巴细胞白血病密切相关。LMO2是细胞中介导转录因子复合物形成的重要接头分子。现对LMO2的分子结构及其在正常和白血病细胞中的调控作用机制的差异作重点介绍。在此基础上还讨论了LMO2成为逆转录病毒介导的基因治疗X染色体连锁的严重联合免疫缺陷综合征过程中成为病毒插入靶位点的可能原因。     

Apoptose et ségrégation méiotique dans les spermatozoïdes d'hommes porteurs de translocations

Men with a chromosomal translocation produce a significant percentage of unbalanced spermatozoa. In order to determine a correlation between chromosomal anomalies and apoptosis in human sperm, we analysed DNA fragmentation and meiotic segregation in sperm from men with a (13;14) Robertsonian translocation. We studied sperm from 12 (13;14) translocation carriers and 9 proven fertile men with a normal karyotype. Meiotic segregation of chromosomes 13 and 14 was analysed using dual-colour fluorescencein situ hybridization with locus-specific probes for chromosomes 13 and 14. Apoptosis in spermatozoa was measured byin situ TUNEL assay. The meiotic segregation study showed a significantly increased frequency of unbalanced spermatozoa for chromosomes 13 and 14 in (13;14) carriers (15.9%) compared to the control population (1.3%) (p=0.00016). The study of apoptosis showed an increase of DNA fragmentation in (13;14) carriers (34.9%) compared to the control population (13.8%) (p=0.0036). This increased apoptosis was observed in spermatozoa presenting an increase of unbalanced chromosomal anomalies concerning chromosomes 13 and 14, but with a predominance of balanced spermatozoa compared to the theoretical risk of meiotic segregation. These results suggest that apoptosis could be involved as a regulatory mechanism to eliminate unbalanced chromosomal spermatozoa in men with a (13;14) Robertsonian translocation.     

Mating between two balanced translocation carriers in two unrelated families

Partial trisomy 9p and a 13/14 translocation occurred in the daughter of a t(5;9)(p15;p12) mother and a t(13;14)(p11;q11) father. Two additional offspring displayed a normal karyotype and a translocation trisomy 13 respectively. Two first cousins, selected for chromosome analysis because of a spontaneous abortion, were found to have an identical translocation t(14;21)(p11;q11). Their second pregnancy was monitored by midtrimester amniocentesis and disclosed a balanced fetus. The different zygotic chromosome constitutions and the counselling problems in the marriages between two balanced translocation carriers are discussed.     

The characterisation of the lymphoma cell line U937, using comparative genomic hybridisation and multi-plex FISH.

The cell line U937, which has been used extensively for studies of myeloid differentiation, bears the t(10;11)(p13;q14) translocation which results in a fusion between the MLLT10 (myeloid/lymphoid or mixed-lineage leukemia [trithorax, Drosophila, homolog]; translocated to 10; alias AF10) gene and the Ap-3-like clathrin assembly protein, PICALM (Clathrin assembly lymphoid myeloid leukaemia). Apart from this translocation, very little is known about the other genetic alterations in this cell line that may represent significant events in disease progression. In this study, conventional G-banding, CGH and M-FISH have been used to characterise fully all of the cytogenetic alterations present in the U937 cell line. M-FISH analysis confirmed the presence of the t(10;11) and an apparently normal copy of both chromosomes 10 and 11. A t(1;5) translocation was observed as well as several unbalanced rearrangements. CGH detected amplifications resulting from duplications of 2q, 6p and 13q. These changes could result in fusion gene products involved in carcinogenesis or the positions of putative oncogenes and tumour suppressor genes. A good correlation between conventional G-banding, CGH and M-FISH was observed.     

(11; 14) translocation in three boys with acute lymphoblastic leukemia of T-cell immunophenotype

Three boys, 12, 15 and 5 years old are presented with acute lymphoblastic leukemia resp. Non-Hodgkin's lymphoma with leukemic transformation. Blast cells could be characterized as being of T-cell origin. Hand mirror variant was the predominant morphologic feature of the blast cells in two patients. Chromosome analysis of the leukemic blast cells revealed a pseudodiploid (modal chromosome number = 46) karyotype in two patients and a pseudotetraploid (modal chromosome number = 92) in one patient. A chromosome translocation (11; 14) with breakpoints at (p 13; q 13) (within the human T-cell receptor alpha chain locus!) was found in the leukemic cells of all three cases plus an additional t (7; 9) (q 22; p 13) in one patient.     

Establishment and characterization of a clonal human T-cell line, MKB-1 derived from a patient with acute myeloblastic leukemia

A human T-cell line, designated as MKB-1, was established by cloning procedures in a suspension culture from a peripheral blood of a 17-year-old female patient with acute myeloblastic leukemia. The immunological marker profile of MKB-1 indicated that unlike a myeloid phenotype of the original leukemic cells, the cells were positive for CD3 (both cell surface and cytoplasm), T cell receptor (TcR) alpha/beta heterodimer, CD4, CD5, CD7, CD10, CD57 (Leu7), SN-1 and the cytoplasmic TcR beta chain. These findings indicate the T cell nature of the established cells. Terminal deoxynucleotidyl transferase (TdT) was also detected in 60%. We did not detect markers of human myeloid and B cell associated antigens, HLA-class II or immunoglobulin chains. Cytogenetic study revealed that the MKB-1 cells had a female hypo-tetraploid karyotype with chromosomal abnormalities including a translocation between chromosomes 10 and 14. The breakpoint of chromosome 14 of this translocation, 14q11.2, is known to be the location of TcR alpha and delta genes; t(10; 14) (q26; q11.2) is a variant type of a T cell neoplasm-associated translocation, t (10; 14) (q24; q11.2). The MKB-1 cell line is unusual in that its T cell characteristics are phenotypically and cytogenetically distinct from the original myeloid leukemia cells.     

Complex chromosomal rearrangement involving chromosomes 11, 13, 14 and 18 resulting in monosomy for 13q32----qter

A five-year-old boy with speech delay, minor facial abnormalities and borderline psychomotor retardation was found to have a complex de novo double translocation involving four chromosomes resulting in monosomy for the segment 13q32----qter. Chromosomes involved were 11, 13, 14, and 18. The translocation between chromosome 11 and 13 was unbalanced with the loss of the segment 13q32----qter. The second translocation between 14 and 18 was apparently balanced.     

Translocation +(7p+; Bq-) associated with recurrent abortion.

A balanced translocation was found in a normal female with a history of four abortions. On the basis of the Giemsa-banding pattern the abnormality was interpreted as to be a translocation of a part of the long arm of chromosome 13 to the short arm of chromosome some 7:t(7;13)(7qter leads to 7p22::13q14 leads to 13qter;13q14 leads to 13pter::7p22 leads to 7 pter). Problems in genetic counseling are discussed with respect to this case.     

The complex translocation (9;14;14) involving IGH and CEBPE genes suggests a new subgroup in B-lineage acute lymphoblastic leukemia

Many subtypes of acute lymphoblastic leukemia (ALL) are associated with specific chromosomal rearrangements. The complex translocation t(9;14;14), a variant of the translocation (14;14)(q11;q32), is a rare but recurrent chromosomal abnormality involving the immunoglobulin heavy-chain (IGH) and CCAAT enhancer-binding protein (CEBPE) genes in B-lineage ALL (B-ALL) and may represent a new B-ALL subgroup. We report here the case of a 5-year-old girl with B-ALL, positive for CD19, CD38 and HLA-DR. A direct technique and G-banding were used for chromosomal analysis and fluorescentin situ hybridization (FISH) with BAC probes was used to investigate a possible rearrangement of the IGH andCEBPE genes. The karyotype exhibit the chromosomal aberration 46,XX,del(9)(p21),t(14;14)(q11;q32). FISH with dual-color break-apartIGH-specific and CEPBE-specific bacterial artificial chromosome (BAC) probes showed a complex t(9;14;14) associated with a deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) and paired box gene 5 (PAX5) at 9p21-13 and duplication of the fusion gene IGH-CEBPE.     

Proximal trisomy 13. A family with balanced reciprocal translocation t(8;13) in seven members and Robertsonian translocation t(13;14) in three members

Summary The cytogenetic analysis of a 12-year-old retarded boy revealed a partial proximal trisomy 13, resulting from a maternal translocation t(8;13). A familial study shows this translocation in seven persons and also a Robertsonian translocation t(13q;14q) in three sons of a t(8;13) father. A review of partial proximal trisomies 13 shows a variability in the phenotypic expression.     

Inherited (13; 14) translocation and reproduction

Summary An inherited translocation chromosome t(13;14) was found in three unrelated families which showed strikingly different types of reproductive disturbances possible associated with the translocation chromosome. Two translocation carrier sisters on the first family had four pregnancies of which one yielded a severely malformed child with a translocation D trisomy and three pregnancies terminated in spontaneous abortions. In the second family the translocation carrier mother had had seven spontaneous abortions, one induced abortion and no normal pregnancies. The foetus of the induced abortion had, unexpectedly, a balanced translocation karyotype identical to the mother's. No obvious ill effects of the translocation chromosome were encountered in the third family, in which the translocation was first detected in a girl with typical Down's syndrome. She had 21-trisomy and the t(13;14) translocation. Special attention was paid to the morphology of the translocation chromosome and to the structure of the centromeres using the G-, C- and Q-banding techniques. The translocation chromosome was, however, identical in all three families and it was considered to be a result of an unequal reciprocal translocation of the affected D chromosomes; t(13;14) (q12;p12). The need of prenatal chromosome analyses in pregnancies of D/D-translocation carriers is briefly discussed.

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Zusammenfassung In drei nicht miteinander verwandten Familien wurde ein vererbtes Translokationschromosom gefunden, wobei die Familien auffallend verschiedene Typen von Fortpflanzungsstörungen aufwiesen, die möglicherweise mit dem Translokationschromosom zusammenhängen. Zwei Schwestern der ersten Familie waren Translokationsträger und hatten vier Schwangerschaften, von denen eine ein schwer mißgebildetes Kind mit einer Translokations D-Trisomie erbrachte. Die drei anderen Schwangerschaften endeten mit Fehlgeburten. In der zweiten Familie hatte die Mutter als Translokationsträgerin sieben Fehlgeburten gehabt, davon einen induzierten Abort und keine normalen Schwangerschaften. Der Fetus aus der Schwangerschaftsunterbrechung hatte unerwarteterweise eine balancierte Translokation analog zu der der Mutter. In der dritten Familie, in der die Translokation zuerst bei einem Mädchen mit typischem Down-Syndrom entdeckt worden war, konnte kein schädlicher Effekt des Translokationschromosoms nachgewiesen werden. Das Mädchen hatte eine Trisomie 21 und die t(13;14)-Translokation. Besondere Aufmerksamkeit wurde der Morphologie des Translokationschromosoms und der Struktur der Zentromeren gewidmet. Die G-, C- und Q-Bandentechnik zeigte, daß das Translokationschromosomen in allen drei Familien identisch war. Es war als Ergebnis einer ungleichen reziproken Translokation der betroffenen D-Chromosomen; t(13;14) (q12;p12) anzusehen. Die Frage der Notwendigkeit der pränatalen Chromosomendiagnostik bei Schwangerschaften von D/D-Translokationsträgern wird kurz besprochen.

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Supported by grants from the Foundation for Pediatric Research, the Sigrid Jusélius Foundation, and the National Research Council for Medical Sciences, Finland.     

Meiotic segregation of chromosomes 13 and 14 in sperm of heterozygous Robertsonian translocation der(13;14)(q10;q10) carriers

Meiotic segregation of chromosomes 13 and 14 was assessed by fluorescence in situ hybridization on sperm of five heterozygous carriers of the most frequent Robertsonian translocation der(13;14). Alternate segregation mode was predominant (mean 78.2 ± 5.7%). The prevalence of balanced sperm varied from 69.4 to 86.5%. Adjacent segregation mode was detected in 18.64 ± 4.90% of sperm; 3:0 mode was detected in 2.48 ± 1.20% of sperm. These results are informative for reproductive counseling of Robertsonian translocation der(13;14) carriers providing information for assessment of probability of receiving normal/balanced embryos in assisted reproduction cycles.     

Chromosome analysis of spermatozoa from a male heterozygous for a 13;14 Robertsonian translocation

Summary Cytogenetic analysis of 78 spermatozoa from a man heterozygous for a t(13;14) Robertsonian translocation was performed. R banding was applied for chromosomal identification. Incidence of normal and balanced complements were respectively 50% and 41.3%. Six unbalanced complements (7.7%) were observed, resulting from adjacent segregation. Although alternate segregation is the most common mode of distribution, the possibility of producing unbalanced zygotes exists. The frequency of abnormalities unrelated to the translocation was 16.5% including 12.8% hypohaploïdy, 2.5% hyperhaploidy, and 1.2% of structural aberrations. An excess of t(13;14) X complements was observed (24 with X versus 14 with Y). This may result from the close association between trivalent (13;14) and X chromosome observed in the pachytene spermatocyte nucleus.     

Rearrangement of the c-myc proto-oncogene locus in a cell line of T-lymphoblastic origin

A molecular rearrangement of the proto-oncogene c-myc located downstream of the exon III 3' end has been found in a cell line derived from KE37 cell line established from an acute T-lymphoblastic leukemia. This rearrangement resulted from a chromosomal translocation t(8; 14)(q24; q11). Since the 14q11 chromosomal band has been found to be involved in several T-cell leukemias and lymphomas, the importance of the rearrangement of c-myc discovered in the KE37 cell line lies in the possibility of analyzing chromosome 14 DNA near the breakpoint involved in the translocation.     

Uniparental heterodisomy for chromosome 14 in a phenotypically abnormal familial balanced 13/14 Robertsonian translocation carrier.

A 9-year-old mentally retarded girl with multiple congenital anomalies was found to carry a balanced 13/14 Robertsonian translocation [45,XX,t(13q14q)] which was also present in her father. Her mother carried a balanced reciprocal translocation between chromosomes 1 and 14 [46,XX,t(1;14) (q32;q32)]. Both of her parents were phenotypically normal. Molecular studies were carried out to determine the parental origin of chromosomes 1, 13, and 14 in the patient. Using probes for D14S13 and D14S22, we could show that the patient inherited both chromosomes 14 from her father and none from her mother. Similar studies using probes for chromosomes 1 (D1S76) and 13 (D13S37) loci showed the presence of both maternal and paternal alleles in the patient. Our findings indicate that paternal uniparental heterodisomy for chromosome 14 most likely accounts for the phenotypic abnormalities observed in our patient. It is suggested that uniparental disomy may be the basis for abnormal development in at least some phenotypically abnormal familial balanced-translocation carriers.     

A Yeast Artificial Chromosome Contig That Spans the RB1-D13S31 Interval on Human Chromosome 13 and Encompasses the Frequently Deleted Region in B-cell Chronic Lymphocytic Leukemia

Abnormalities involving chromosome 13 have been reported as the only cytogenetic change in B-cell chronic lymphocytic leukemia (BCLL). Deletions are the most common cytogenetic abnormality and always involve 13q14, but when translocations are seen, the consistent breakpoint is always in 13q14. It is now established that deletions, distal to the RB1 gene in 13q14, are invariably associated with these translocations. We have recently described the smallest such deletion from a series of rearrangements from these tumors isolated in somatic cell hybrids, which spans approximately 1 Mb. In this report, we present the results of a series of a chromosome walking experiments using YACs and have been able to span this small deletion, which must contain the gene that is frequently deleted in BCLL. Four probes from 13q14 (RBI-mgg15-D13S25-D13S31) were used to isolate corresponding YACs for each of the markers. The chromosomal location of these YACs was verified using FISH, which also demonstrated their nonchimeric nature. Vectorette end rescue was then used to demonstrate the overlap of the YACs and to isolate new clones to complete the contig. The extremes of the contig were shown to cross the chromosome 13 translocation breakpoints isolated in somatic cell hybrids that carry the derivatives of chromosome 13 involved in the smallest BCLL deletion. This YAC contig covers the entire deletion and will prove a valuable resource to begin isolating genes from this region. In addition, we have isolated YACs corresponding to the RB1 locus, which extends the contig over a 3.8-cM distance on the chromosome.