1/41. Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical research Council (MRC) adult Leukaemia Working Party.Acute promyelocytic leukaemia (APL) is characterized by the t(15;17) leading to the formation of PML-RARalpha and RARalpha-PML fusion genes; this rearrangement has been considered both diagnostic for, and restricted to, this subtype of acute myeloid leukaemia (AML FAB M3). We describe two cases of AML with the t(15;17) associated with a PML/RARalpha rearrangement which lacked typical APL morphology, classified as FAB M1 and M2 respectively. In both cases morphological review revealed small populations of cells which exhibited some features associated with APL. In the case classified as M1, PML immunofluorescence studies revealed the classic microparticulate nuclear staining pattern as observed in typical cases of APL with the t(15;17). Similarly, blasts from this case were found to be sensitive to ATRA in vitro as determined by NBT reduction test and by normalization of the PML nuclear body staining pattern. To determine the frequency of PML/RARalpha rearrangements in FAB subtypes other than M3, 530 patients from the MRC AML trials were screened using nested RT-PCR. Only one individual, initially classified as M5 with a normal karyotype, was found to have a PML/RARalpha rearrangement. The diagnosis was revised to M3 variant on subsequent morphological review. In conclusion, this study demonstrates that, in rare cases, the t(15;17) is not restricted to patients with M3 morphology as defined by current FAB criteria. Therefore, although we consider cytogenetic analysis of newly diagnosed cases of AML to be mandatory, our data suggests that routine molecular screening for PML/RARalpha rearrangements is not justified and should be reserved for those cases displaying features which may be suspicious of APL even if such cells comprise only a minority of the total population.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
2/41. Eosinophilic myelodysplasia transforming to acute lymphoblastic leukaemia.A 43 year old male presented with a marked eosinophilia and associated systemic symptoms. A diagnosis of myelodysplasia was made on the basis of bone marrow morphology and karyotype. Over a 12 month period the disease transformed into acute lymphoblastic leukaemia, confirmed by flow cytometry, cytochemistry, and immunohistochemistry. karyotyping was abnormal with 5q- and -7 which persisted from diagnosis through to blastic transformation. He died following initial induction chemotherapy. Eosinophilic myelodysplasia is an uncommon condition in haematological practice and no previous report of lymphoblastic transformation has been found.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
3/41. Establishment of novel human esophageal cancer cell line in relation to telomere dynamics and telomerase activity.The telomere and the telomerase in human esophageal cancer are not yet completely understood. The regulatory mechanism of telomerase activity and telomere dynamics has drawn considerable attention. It is generally assumed that when telomerase has been activated, no further telomere shortening should ensue; however, a much more complex pattern of telomere dynamics may exist in telomerase-positive cancer cells. A novel human esophageal cancer cell line (KAN-ES) was established and characterized. Using KAN-ES and its serially passaged subclones up to the 55th generation, we determined the alteration of telomere length (TRF), telomerase activity (TA), telomerase rna expression (hTR), population doubling time, karyotype, and cytokeratin 14 expression during the process of establishing a cancer cell line. We found that the TRF was maintained between 4.0 and 5.0 kb during the serial passages, despite sustained high TA (assessed by an in vitro TRAP assay). No close relationships were found among TRF, TA, and hTR expression. TA and telomere dynamics were not associated with cellular growth ability and differentiation. However, the number of population doublings showed significant correlations with both the TA and doubling times. In conclusion, these dissociations between telomere dynamics and TA support the existence of additional controls on TRF in cancer cells. KAN-ES and its restored subclones should prove a valuable resource for esophageal cancer research.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
4/41. Need for an accurate molecular diagnosis to assess the donor origin of leukemia relapse after allogeneic stem cell transplantation.BACKGROUND AND OBJECTIVES: leukemia relapse occurring in donor cells after allogeneic hematopoietic stem cell transplantation has been reported in rare cases. cytogenetic analysis and molecular probing of variable number of tandem repeats (VNTRs) have been used to confirm this unusual event in the few cases so far reported in the literature. The aim of this study was to demonstrate that extensive molecular characterization of leukemic cells at diagnosis and relapse may be necessary to avoid many technical pitfalls possibly leading to an erroneous diagnosis of leukemia relapse in donor cells after allogeneic transplantation. DESIGN AND methods: We report the case of a 49- year old man who received an allogeneic transplantation from his HLA-identical sister because of BCR-ABL acute lymphoblastic leukemia (ALL). After having achieved complete hematologic and molecular remission, two years later an overt leukemia relapse occurred with cytogenetic findings suggesting a leukemia relapse in donor cells. The donor or patient origin of leukemic cells at relapse was further investigated by fluorescence in situ hybridization (FISH) karyotyping, reverse transcription (RT) polymerase chain reaction (PCR) analysis of BCR-ABL chimeric transcripts, PCR amplification of several VNTRs and the y chromosome-specific DYS14 sequence and finally by amplification, cloning and sequencing of the CDRIII region of the immunoglobulin heavy chain (IgH) gene. RESULTS: At the time of relapse, conventional and FISH karyotyping revealed the presence of a Phl chromosome and a female karyotype in all the 25 metaphases analyzed and PCR amplification of the y chromosome-specific DYS14 sequence was negative. Moreover, the molecular evaluation of hematopoietic chimerism performed by the NZ-22 VNTR allowed us to demonstrate that at the time of relapse, a consistent proportion of hematopoietic cells was of donor origin. However, the molecular cloning and sequencing of the CDRIII region of the immunoglobuin heavy chain (IgH) gene rearrangement in leukemic blasts at diagnosis and relapse demonstrated their identity thus formally proving the patient origin of both leukemic clones. INTERPRETATION AND CONCLUSIONS: While the simplest interpretation of the apparent female karyotype at relapse is the consequence of a loss of the y chromosome which in leukemic blasts took place along with duplication of an X-chromosome, this case strongly emphasizes the need for accurate and extensive molecular characterization to prove the donor origin of a leukemia relapse after allogeneic transplantation.- - - - - - - - - - ranking = 2keywords = karyotype (Clic here for more details about this article) |
5/41. Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia: report of an adult case and review of the literature.Lineage switch from AML to ALL is an extremely rare phenomenon, and we report the case of an adult diagnosed with AML at 46 years of age who relapsed with ALL. At initial diagnosis, blast cell morphology and immunophenotyping were consistent with the diagnosis of M4-AML. Complete remission was achieved, and the patient underwent autologous BMT. At relapse, six months after ABMT, blast cells were different from those seen at initial diagnosis, for morphology (L2-ALL), cytochemistry, and immunophenotyping. The karyotype was normal at both diagnosis and relapse. No evidence of bcr-abl fusion genes was found by RT-PCR. Monoclonal IgH and TCR gamma gene rearrangement were evidenced by PCR analysis at relapse but not on blast cells at AML diagnosis.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
6/41. Leukemic transformation with trisomy 8 in essential thrombocythemia: a report of four cases.karyotype analysis of bone marrow samples was performed in 20 cases of essential thrombocythemia (ET) at the time of diagnosis. Three patients had karyotype abnormalities at the time of diagnosis; trisomy 8, deletion of Y, and del(9)(q?) in each. The patient who had trisomy 8 at the time of diagnosis underwent myeloid blastic transformation in 35 months. Three patients whose karyotypes were normal at the time of diagnosis developed a chromosome abnormality with trisomy 8 when they developed myeloid blastic transformation 38, 79 and 86 months after initial diagnosis of ET. Two patients with blastic transformation had been treated with busulfan, one with hydroxyurea and one with methyl-6-[3-(2-chloroethyl)-3-nitorosoureidol]-6-deoxy-alpha-D-glucopyranoside (MCNU). It is suggested that progression of the disease may have increased the incidence of trisomy 8 and the development of leukemic transformation.- - - - - - - - - - ranking = 2keywords = karyotype (Clic here for more details about this article) |
7/41. Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis.A hyperdiploid karyotype is found in 30% of B-cell precursor acute lymphoblastic leukemias in childhood. The time of nondisjunction of chromosomes leading to hyperdiploidy during leukemogenesis is unknown. We used the 3 clonotypic immunoglobulin heavy chain (IgH) gene rearrangements as molecular markers for each of the 3 chromosomes 14 in a case with hyperdiploid acute lymphoblastic leukemia to define the order of events-namely, somatic recombination and nondisjunction of chromosomes-during leukemia development. A partial sequence homology of the incomplete DJ(H) rearrangement with 1 of the 2 nonfunctional VDJ(H) rearrangements suggests that the doubling of chromosomes had occurred after this DJ(H) rearrangement and thus during early B-cell differentiation. The occurrence of the nondisjunction of chromosomes as well as ongoing rearrangement processes in utero were confirmed by the presence of all 3 IgH rearrangements in neonatal blood spots, providing the first evidence that hyperdiploidy formation is an early event in leukemogenesis in these leukemias.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
8/41. Transformation in chronic granulocytic leukaemia. Different blast cell clones in different anatomical sites.A 45-year-old female developed blastic metamorphosis in chronic granulocytic leukaemia after 52 months of chronic phase. During the subsequent 6--7 months, lymphosarcomatous enlargements of various lymph nodes developed. The blast cells in lymph nodes differed morphologically from those in bone marrow and blood, being 'lymphoid' non-B, non-T, non-ALL cells. The karyotype of all metaphases from one lymph node was 47,XX, 21(Ph1 ) being identical to the karyotype of medullary cells. However, the karyotype of all blasts from another lymph node was 47,XX, mar(Ph1 ). It is likely that the local micro-environment controlled the clonal differentiation of these subpopulations which had originated from the same Ph1-positive multipotent stem cell. In lymph nodes and other extramedullary sites blasts were primitive without differentiation, but a myeloid differentiation in the bone marrow was demonstrated morphologically and cytochemically.- - - - - - - - - - ranking = 3keywords = karyotype (Clic here for more details about this article) |
9/41. del11(p11-13) with overexpression of Wilms' tumor gene during leukemic transformation of myelodysplastic syndrome.We report a case of leukemic transformation from myelodysplastic syndrome (MDS) with a sole chromosome abnormality of del11(p11-13). The patient had been diagnosed as having MDS (refractory anemia with excess of blast cells, RAEB) in May 1998. At that time, cytogenetic analysis of bone marrow cells showed a normal karyotype. The patient received sequential chemotherapy with low-dose cytosine arabinoside (AraC) and macrophage colony-stimulating factor (M-CSF). Complete remission was obtained with this treatment, but the disease gradually progressed after June 1999. Cytogenetical analysis showed del11(p11-13) in 6 of 40 cells analyzed at that time, and the disease had evoluted to overt leukemia in December 1999 with a gradual increase in the abnormal clone. Furthermore, mRNA of the WT1 gene located at chromosome 11p13 was overexpressed during leukemic transformation, whereas it was not detected at the time of the initial diagnosis of MDS (RAEB) in May 1998. It was thought that this chromosome deletion and overexpression of WT1 resulted in the leukemic transformation in this patient. This is the first case report of del11(p11-13) being considered to be the primary cause of leukemic transformation from MDS.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
10/41. Multilineage involvement in hypereosinophilic syndrome terminating in granulocytic sarcoma and leukaemic transformation with trisomy 8.We report a patient with hypereosinophilic syndrome (HES), which, 8 years later, transformed into granulocytic sarcoma in the brain and, subsequently, into acute myelocytic leukaemia. Repeated chromosome analyses showed a normal karyotype, until the time of leukaemic transformation when trisomy 8 was confirmed in cells from the bone marrow and cerebrospinal fluid. The combined techniques of May-Grunwald-Giemsa staining and fluorescence in situ hybridization identified trisomy 8 not only in blasts and eosinophils but also in neutrophils and erythroblasts. Our observation suggests that HES is a multilineage myeloproliferative disorder involving precursors of at least the eosinophil, neutrophil and erythroid lineages.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
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