Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11;17)(q23;q21) in a patient with acute promyelocytic leukemia.

Cytogenetic study of a patient with acute promyelocytic leukemia (APL) showed an unusual karyotype 46,xy,t(11;17) (q23;21) without apparent rearrangement of chromosome 15. Molecular studies showed rearrangements of the retinoic acid receptor alpha (RAR alpha) gene but no rearrangement of the promyelocytic leukemia gene consistent with the cytogenetic data. Similar to t(15;17) APL, all-trans retinoic acid treatment in this patient produced an early leukocytosis which was followed by a myeloid maturation, but the patient died too early to achieve remission. Further molecular analysis of this patient showed a rearrangement between the RAR alpha gene and a newly discovered zinc finger gene named PLZF (promyelocytic leukemia zinc finger). The fusion PLZF-RAR alpha gene found in this case, was not found in DNA obtained from the bone marrow of normals, APL with t(15;17) and in one patient with AML-M2 with a t(11;17). Fluorescence in situ hybridization using a PLZF specific probe localized the PLZF gene to chromosomal band 11q23.1. Partial exon/intron structure of the PLZF gene flanking the break point on chromosome 11 was also established and the breakpoint within the RAR alpha gene was mapped approximately 2 kb downstream of the exon encoding the 5' untranslated region and the unique A2 domain of the RAR alpha 2 isoform.

JEM-1, a novel gene encoding a leucine-zipper nuclear factor upregulated during retinoid-induced maturation of NB4 promyelocytic leukaemia.

Retinoid-induced proliferation causing hyperleukocytosis is a severe complication of retinoid therapy in t(15;17) acute promyelocytic leukaemia. The molecular basis of this phenomenon is unknown. It is possible that the transiently enhanced cell proliferation results from RA-induction of growth regulatory genes. Using Differential Display of cDNAs from NB4 cells we have identified Jem, a novel gene transcript which is upregulated by retinoids during the early proliferative response in maturating cells but not in resistant cells. A 2.7 kb cDNA was cloned and sequenced. The open reading frame contains a 400 amino acid sequence corresponding to a novel 45 kDa basic protein (pI 8.9). The JEM DNA sequence is detected by FISH on human chromosome 1 at q24. The Jem peptide sequence shows a 'leucine-zipper' dimerisation motif with limited homology to Fos/Jun and ATF/CREB proteins and several putative phosphorylation sites. An atypical basic region may correspond to an unknown DNA-binding domain. The C-terminal end of Jem spans a long stretch featuring a PEST motif. After transfection into COS cells, the Jem protein shows a ponctuated nuclear localisation. We hypothesise that this novel nuclear factor may act as a transcription factor, or a coregulator, involved in either cell growth control and/or maturation.

Whole arm translocation t(17;18): a non-random abnormality of myeloid cell proliferation.

Whole arm translocation t(17;18) was detected in two patients, one with acute monocytic leukemia and the other with acute transformation of chronic myelocytic leukemia. Dual-color fluorescence in situ hybridization (FISH) to interphase nuclei with alphoid probes specific to chromosomes 17 and 18 showed the presence of two very close spots. This feature was interpreted as the conservation of the pericentromeric region of the two chromosomes involved in the translocation. The present cases add to eight previously reported other patients with whole arm translocation t(17;18) (one with FISH studies). Since these patients had either myeloid leukemia or myelodysplastic syndrome, it is suggested that the t(17;18)(p10;q10) translocation is a new non-random abnormality associated with myeloid cell proliferations.

Faconi anemia and bone marrow clonal chromosome abnormalities.

Clonal chromosome abnormalities were detected in bone marrow cells of 20 patients with Fanconi anemia investigated at various stages of the disease. Two presented with acute leukemia, six with myelodysplastic syndrome, and 12 had minor or no morphological abnormalities of hematopoietic cells. Abnormalities of chromosome 7 were detected in nine patients (monosomy, isochromosome, or other structural rearrangement), and chromosome 1 was rearranged in four. The types and the significance of clonal chromosome abnormalities which may be present without apparent evolution toward acute leukemia or myelodysplastic syndrome in Fanconi anemia patients are discussed.

Chromosomal rearrangement on chromosome 11q14-q21 in T cell acute lymphoblastic leukemia.

Deletion and translocation involving the bands 11q14 and 11q21 have been detected in five patients with T cell acute lymphoblastic leukemia (ALL). The breakpoint on chromosome 11 was on the same band as that previously described in some acute nonlymphocytic leukemias: monocytic or myelomocytic. The existence of a new nonrandom rearrangement involving bands 11q14-q21 is postulated in ALL. An unusual rearrangement on 11q13 in a patient with T cell ALL is also reported.

Translocation t(11;11)(q13;q23) and HRX gene rearrangement associated with therapy-related leukemia in a child previously treated with VP16.

A child with acute myelomonocytic leukemia, bone marrow eosinophilia and inv(16) received first-line therapy including etoposide (VP-16). Cytopenia and monocytosis appeared 7 months after complete remission while the child was treated with maintenance chemotherapy. Blood abnormalities persisted after discontinuation of treatment. Nine months after complete remission, t(11;11)(q13;q23) and HRX rearrangement were detected. Five months later, overt leukemia of monocytic type occurred. The responsibility of VP-16 therapy in this treatment-related acute myelocytic leukemia is discussed.

Distinct MLL gene rearrangements associated with successive acute monocytic and lymphoblastic leukemias in the same patient.

A patient with acute monocytic leukemia (AMoL) and t(6;11)(q27;q23) developed acute lymphoblastic leukemia (ALL) and t(4;11)(q21;23), 10 months after complete remission of the AMoL. The MLL gene, normally located at band 11q23, appeared differently rearranged in the cells of these two leukemias, showing a different origin for the two malignant clones. The responsibility of etoposide, used in treatment of the AML, in the occurrence of the ALL is probable in this patient.

5q- anomaly in acute lymphoblastic leukemia.

We report two new cases of common acute lymphoblastic leukemia (ALL) with 5q-. This abnormality, which is uncommon in ALL, was previously reported in 14 cases of ALL of various subtypes and appears to occur less frequently in common ALL than in other types of ALL.

Translocation (2;3)(p22;q28) is associated with myeloid disorders.

Chromosome studies carried out in two children with acute myeloblastic leukemia (AML, M2) showed a t(2;3)(p22;q28). This abnormality was associated with monosomy 7 and del(12)(p12) in the first patient and was found only in relapse in the second patient. Comparison with the other previously published t(2;3) suggests that this translocation is a nonrandom abnormality involving a pluripotent stem cell and occurring as a secondary chromosome abnormality in AML.

Partial deletion of chromosome 2 in non-Hodgkin lymphoma.

Six patients with non-Hodgkin malignant lymphoma (NHL) in a series of 151 cases showed partial deletion of chromosome 2 when studied cytogenetically. Three had deletions of bands 2p14-p22 and three others had a deletion of bands 2q22-q24 in common. The deletions were associated with other abnormalities in each case and were not associated with a particular subtype of NHL. These deletions are secondary, apparently nonrandom, new abnormalities associated with NHL.

Loss of chromosome 22 in patients with refractory anemia with excess of blasts (RAEB) in transformation and acute leukemia after RAEB.

We report studies of 12 patients with refractory anemia and excess of blasts in transformation (RAEB-t) and 17 with acute myeloblastic leukemia (AML) after RAEB. Besides chromosome 5 and 7 abnormalities, five patients with complex karyotypic changes had monosomy 22. This association is discussed in relation to the hypothesis of a suppressor gene located on chromosome 22.

Deletion of (7p13p14) in non-Hodgkin's lymphoma.

Deletion of the short arm of chromosome 7 at 7(p13p14) has been occasionally reported in non-Hodgkin's malignant lymphoma (NHL). The inclusion of this abnormality within the list of nonrandom changes awaited further data. We report three partial deletions of 7p with breakpoint at 7p13, found in various subtypes of NHL, and one deletion covering these bands (7p11 to 7p15). The association of 7p- with other chromosomal changes in the same NHL suggests that partial 7p deletion is a nonrandom secondary abnormality.

Consistent DNA losses on the short arm of chromosome 1 in a series of malignant gastrointestinal stromal tumors.

Fourteen malignant gastrointestinal stromal tumors (GISTs), characterized by immunohistochemistry, were analyzed by comparative genomic hybridization (CGH). The most striking feature was the detection of consistent DNA losses on the short arm of chromosome 1 in these 14 malignant tumors. Additional recurrent imbalances were also found: significant gains, which could be indicative of tumor progression, were frequent on the long arm of chromosome 1, as were losses of DNA copy number detected in chromosomes 13, 14, 15 and 22.

Abnormalities of chromosome 18 in myelodysplastic syndromes and secondary leukemia.

Monosomy 18 and partial deletion of 18q are nonrandom events in myelodysplastic syndromes (MDS) and secondary acute myeloblastic leukemia (sAML). They are part of complex chromosome abnormalities, as shown in the present study of six patients with MDS and sAML. We compared occurrence of chromosome 18 abnormalities in these syndromes with that in de novo AML.

Cytogenetic studies of 44 T-cell acute lymphoblastic leukemias.

Cytogenetic studies on 44 patients with T-cell acute lymphoblastic leukemia (ALL) were reported. The incidence of leukemia without detectable chromosomal changes was 25%. Hyperdiploidy with more than 50 chromosomes was found in only one patient. Previously described nonrandom abnormalities like 6q-, 9p-, and 12p- were observed, and it was confirmed that they are not specific for a particular type of ALL. The incidence of chromosomal rearrangements on chromosomes 7 and 14 where the T-cell receptor gene loci are located was 36% of those with abnormal karyotypes and 27% of the total. This was clearly different from the frequency of rearrangements of these bands found in T-cell lymphoma. Finally, a rearrangement on bands 11q14-q21 was detected in five cases.

Cytogenetic studies on acute nonlymphocytic leukemia in relapse.

Karyotypic abnormalities were compared in 42 acute nonlymphocytic leukemia patients at diagnosis and in relapse. Clonal changes were observed in 21 cases. The types of changes were the appearance of clonal abnormalities in relapse in four patients without clonal changes at diagnosis, the detection of new abnormalities superimposed on preexisting ones in 11 cases, and the selection of an abnormal clone in six others. Nonclonal structural abnormalities, mainly involving chromosomes 17 and 12p, were detected in relapse in 17 patients, compared to seven at diagnosis. The appearance of totally new clonal changes at relapse and the role of individual sensitivity to chemotherapy are discussed.

Cytogenetic studies on 519 consecutive de novo acute nonlymphocytic leukemias.

Cytogenetic studies were performed in the same laboratory on 519 untreated cases of de novo acute nonlymphocytic leukemia (ANLL) between 1977 and 1985. The overall incidence of clonal chromosome abnormalities was 54.3%; higher in children (67.5%) than in adults (50.4%). The distribution of chromosome abnormalities was uneven, according to the categories of the FAB nomenclature. The highest frequency of chromosome changes was observed in ANLL-M3 and the lowest in M1 and M6. The frequency of specific chromosome abnormalities and of their associated changes were also estimated. Monosomy 7 was detected in three patients with acute megakaryocytic leukemia (M7). Six cases with two abnormal chromosomally unrelated clones were observed and six constitutional chromosome abnormalities were detected. A clearer knowledge of the incidence of various chromosomal changes in ANLL seems necessary for better differentiation between the so-called primary and secondary chromosome abnormalities and for prognostic evaluation.

Fluorescence in situ hybridization on metaphase chromosomes with biotinylated probes. In situ hybridization, biotin labeling, cosmids, gene mapping, oncogene amplification.

In situ hybridization on metaphase chromosomes have been used to localize specific nucleic acid sequences. Initially, the nucleic acid probes were labeled isotopically. Over the past few years, non isotopic techniques have considerably progressed, and are being applied to a large spectrum of biological and clinical problems.

Secondary nonrandom chromosomal abnormalities of band 13q34 in Burkitt lymphoma-leukemia.

Clonal abnormalities of the long arm of chromosome 13 were detected in 9 of 54 patients with Burkitt lymphoma-leukemia. All abnormalities involved band 13q34, in three patients as t(1;13). The 13q34 abnormalities are thus the second most frequent secondary chromosomal abnormalities, after those of chromosome I, in these lymphoid proliferations.

[Partial "de novo" trisomy 10q (author's transl)]. / Trisomie 10 q partielle de novo

A partial 10q trisomy due to a de novo t(10;22) translocation is reported. The comparison with other published cases of partial 10q trisomy leads to the description of a particular syndrome essentially due to a trisomy for bands 10q24 to 10q26.