Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis.

Tumorigenesis in rodents, as well as in humans, has been shown to be a multistep process, with each step reflecting an altered gene product or gene regulatory process leading to autonomy of cell growth. Initial genetic mutations are often associated with dysfunctional growth regulation, as is demonstrated in several transgenic mouse models. These changes are often followed by alterations in tumor suppressor gene function, allowing unchecked cell cycle progression and, by genomic instability, additional genetic mutations responsible for tumor metastasis.

Multicolor karyotyping in acute myeloid leukemia.

Cytogenetic data have significantly contributed to our understanding of the heterogeneity of acute myeloid leukemia (AML). In AML, numerous recurrent chromosomal aberrations have been identified, and several of them, e.g.

Reciprocal DNA topoisomerase II cleavage events at 5'-TATTA-3' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing.

Few t(9;11) translocations in DNA topoisomerase II inhibitor-related leukemias have been studied in detail and the DNA damage mechanism remains controversial. We characterized the der(11) and der(9) genomic breakpoint junctions in a case of AML following etoposide and doxorubicin. Etoposide-, etoposide metabolite- and doxorubicin-induced DNA topoisomerase II cleavage was examined in normal homologues of the MLL and AF-9 breakpoint sequences using an in vitro assay.

MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site.

We examined the MLL translocation in two cases of infant AML with X chromosome disruption. The G-banded karyotype in the first case suggested t(X;3)(q22;p21)ins(X;11)(q22;q13q25). Southern blot analysis showed one MLL rearrangement.

Spectral karyotyping and fluorescence in situ hybridization detect novel chromosomal aberrations, a recurring involvement of chromosome 21 and amplification of the MYC oncogene in acute myeloid leukaemia M2.

Recurring chromosomal aberrations are of aetiological, diagnostic, prognostic and therapeutic importance in acute myeloid leukaemia (AML). However, aberrations are detected in only two thirds of AML cases at diagnosis and recurrent balanced translocations in only 50%. Spectral karyotyping (SKY) enables simultaneous visualization of all human chromosomes in different colours, facilitating the comprehensive evaluation of chromosomal abnormalities.

Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms.

Jumping translocations (JTs) and segmental jumping translocations (SJTs) are unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to multiple recipient chromosomes. In leukemia, where JTs have been predominantly observed, the donor segment (usually 1q) preferentially fuses to the telomere regions of recipient chromosomes. In this study, spectral karyotyping (SKY) and FISH analysis revealed 188 JTs and SJTs in 10 cell lines derived from carcinomas of the bladder, prostate, breast, cervix, and pancreas.

Simultaneous immunomagnetic CD34+ cell selection and B-cell depletion in peripheral blood progenitor cell samples of patients suffering from B-cell non-Hodgkin's lymphoma.

The reduction of residual tumor cells is one of the main targets of leukapheresis product (LP) processing. Immunomagnetic enrichment/selection of CD34+ progenitor cells (Baxter Isolex 300i) can achieve a reduction of contaminating B-cells of approximately 2-3 logs in B-cell non-Hodgkin's lymphoma patients. Specific release of the enriched CD34+ cells (stem cell releasing agent PR34+; Baxter) and the use of antibody-coated immunobeads targeted against B-cell markers (CD10, CD19, CD20, CD22, CD23, and CD37) during this procedure allows the GMP-like simultaneous capture of residual B cells within a closed system.

Spectral Karyotyping (SKY) of Hematologic Malignancies.

The discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) by Novell and Hungerford in 1960 (1), the subsequent clarification of this chromosomal abnormality as areciprocal translocation t(9;22)(q34;q1 1) by Rowley in 1973 (2), the identification of the genes involved at the translocation breakpoints (3,4), and ultimately the demonstration of the leukemogenic activity of the resulting fusion product (5), represent hallmarks for our understanding of malignant diseases as genetic disorders. The elucidation of the Philadelphia translocation emphasizes the importance of cytogenetic analysis of hematologic malignancies. Clarification of this chromosomal aberration as a reciprocal translocation became only possible after the development of cytogenetic banding techniques by Caspersson et al.

Acute myelogenous leukemia after treatment for malignant germ cell tumors in children.

Purpose: To identify the long-term sequelae of therapy for malignant germ cell tumors (GCTs).

Patients And Methods: Between 1980 and 1998, 1,132 patients were prospectively enrolled onto the German nontesticular GCT studies. A total of 442 patients received chemotherapy using combinations of the drugs cisplatin, ifosfamide, etoposide, vinblastine, and bleomycin, and 174 patients were treated with a combination of chemotherapy and radiotherapy.

Analysis of B-cell neoplasias by spectral karyotyping (SKY).

B-cell neoplasias represent a heterogeneous group of diseases, including acute lymphocytic leukemia (ALL) and the broad spectrum of non-Hodgkin's lymphomas (NHL). Conventional cytogenetic analysis has revealed specific chromosomal aberrations in ALL as well as in NHL. Spectral karyotyping (SKY) is a novel molecular cytogenetic technique which allows the visualization of all human chromosomes in different colors, therefore greatly facilitating the recognition of chromosomal aberrations.

Efficacy and safety of simultaneous immunomagnetic CD34+ cell selection and breast cancer cell purging in peripheral blood progenitor cell samples used for hematopoietic rescue after high-dose therapy.

We have established a new simultaneous positive/negative selection procedure using the Baxter Isolex 300i system. We tested its tumor cell (TC) purging efficacy by tumor contamination tests ex vivo and its safety in a group of 17 breast cancer (BC) patients by measuring hematopoietic recovery after high-dose (HD) therapy and autologous stem cell rescue with the selected cells. Tumor contamination tests resulted in a TC depletion of 4.

Ex vivo expansion of human umbilical cord blood does not lead to co-expansion of contaminating maternal mononuclear cells.

One of the main limiting factors for increased use of human umbilical cord blood (UCB) in adult allogeneic transplantation is the small number of progenitor cells that can be collected and infused. Ex vivo expansion of UCB might help to overcome this limitation. Whether an expansion of UCB cells will also lead to co-expansion of contaminating maternal cells, and thus may alter graft characteristics and lead to an increased incidence of GVHD, has not been looked at so far.

Is there a place for 2-CDA in the treatment of B-CLL?

There is no doubt about 2-CDA being a very potent lymphotoxic agent that displays high efficacy in the treatment of CLL. It interferes with the intranuclear machinery of DNA regulation, and causes death to proliferative active, as well as resting lymphocytes. Interruption of crucial pathways that are evident for cell survival translates into high clinical response rates in CLL.

[Experiences with modified BFM protocols in the treatment of children with acute lymphoblastic leukemia (ALL) in East Germany 1981-1991].

Between September and August 1991 818 previously untreated children and adolescents up to 18 years of age with acute lymphoblastic leukemia were entered into two modified BFM-protocols. Patients with B-ALL were excluded. From 1981 to 1987 524 patients were entered into the randomized multicenter study ALL VII/81 (modified ALL-BFM 81 protocol).

[Diagnostic evaluation of skeletal scintigraphy in comparison to roentgen studies in histiocytosis X in childhood. Case report].

We have compared whole body skeletal scintigraphy with X-ray examination in 15 children suffering from histiocytosis X, 14 of whom also showed involvement of the skeleton. In 9 of 20 cases, relapses, included, involvement of the skeleton was found both in scintigraphy and X-ray examination. In 7 cases only X-ray examinations have revealed lessons, which could not be proved by scintigraphy.

Improved treatment results in childhood acute nonlymphoblastic leukemia with the BFM-AML protocol 78 in a multicenter study in the GDR.

Eighty-seven children with acute nonlymphoblastic leukemia were treated with the AML protocol BFM 78 between June 1979 and February 1986 in a multicenter study in the GDR. Seventeen children (20%) died from early complications, eight did not respond to therapy. Fifty-eight patients (70%) achieved a complete remission.