Background The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma.Design and Methods We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling.Results A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p
Abnormalities of the long arm of chromosome 1 (1q) represent the most frequent secondary chromosomal aberrations in Burkitt lymphoma (BL) and are observed almost exclusively in EBV-negative BL cell lines (BL-CLs). To verify chromosomal abnormalities, we cytogenetically investigated EBV-negative BL patient material, and to elucidate the 1q gain impact on gene expression, we performed qPCR with six 1q-resident genes and analyzed miRNA expression in BL-CLs. We observed 1q aberrations in the form of duplications, inverted duplications, isodicentric chromosome idic(1)(q10), and the accumulation of 1q12 breakpoints, and we assigned 1q21.2-q32 as a commonly gained region in EBV-negative BL patients. We detected MCL1, ARNT, MLLT11, PDBXIP1, and FCRL5, and 64 miRNAs, showing EBV- and 1q-gain-dependent dysregulation in BL-CLs. We observed MCL1, MLLT11, PDBXIP1, and 1q-resident miRNAs, hsa-miR-9, hsa-miR-9*, hsa-miR-92b, hsa-miR-181a, and hsa-miR-181b, showing copy-number-dependent upregulation in BL-CLs with 1q gains. MLLT11, hsa-miR-181a, hsa-miR-181b, and hsa-miR-183 showed exclusive 1q-gains-dependent and FCRL5, hsa-miR-21, hsa-miR-155, hsa-miR-155*, hsa-miR-221, and hsa-miR-222 showed exclusive EBV-dependent upregulation. We confirmed previous data, e.g., regarding the EBV dependence of hsa-miR-17-92 cluster members, and obtained detailed information considering 1q gains in EBV-negative and EBV-positive BL-CLs. Altogether, our data provide evidence for a non-random involvement of 1q gains in BL and contribute to enlightening and understanding the EBV-negative and EBV-positive BL pathogenesis.
7062 Background: As main actors in the generation of new blood vessels, endothelial progenitor cells have been intensely investigated during the past years. The detection of Philadelphia chromosome positive vascular endothelial cells in CML patients confirmed the existence of adult hemangioblasts with both hematopoietic and endothelial developmental potential (Lancet 2000;355:1688–91). To further investigate the origin of endothelial progenitor cells, we analyzed blood outgrowth endothelial cells from Philadelphia chromosome positive CML patients. Methods: OECs have been generated from the peripheral blood (PB) of Philadelphia chromosome positive CML patients (n=16) and healthy donors (n=300). The OEC clones have been analyzed for their proliferative potential, expression of endothelial markers by FACS analysis and presence of the BCR/ABL fusion gene by FISH and PCR. Results: A 10-fold higher frequency of OECs was found in PB of CML patients compared to healthy donors (7.2 and 0.7/108 MNCs, respectively, p<.0001). With an average of 26 total cell doublings, the CML OECs had an increased proliferative potential vs only 20 total cell doublings in healthy donors (p<.0001). Expression of endothelial markers by OECs, as analyzed by FACS, proved their endothelial nature. Remarkably, the FISH and PCR analysis of all 12 examined OEC clones from CML patients were negative for the BCR/ABL fusion gene though none of the analyzed patients was in more than minor cytogenetic remission and the mean frequency of Ph+ cells in PB or seperated CD34+ cells was 99% and 82% (n=14 and n=8, respectively). Conclusions: OECs are not clonally related to hematopoietic progenitor cells harbouring the BCR/ABL translocation. Hence, a putative common precursor of OECs and hematopoietic cells must represent a very early stem cell which is still BCR/ABL negative. A hierarchy of endothelial cells comparable to the hematopoietic system has been described because of different frequencies and proliferative potentials between OECs from umbilical cord and adult PB (Blood 2004;104:2752–60). We postulate that in contrast to OECs from healthy donors, the clones from CML patients represent a collective of more immature OECs probably being mobilized by pro-angiogenic cytokines such as VEGF, which are actively secreted by BCR/ABL+ cells. No significant financial relationships to disclose.
We report a patient with refractory diffuse large B-cell lymphoma who developed irreversible, severe spinal neurotoxicity after concurrent treatment with intrathecal and systemic cytarabine. Shortly after concomitant administration of intrathecal triple therapy (MTX, dexamethasone and cytarabine) and high-dose systemic cytarabin (R-DHAP protocol) the patient lost control of bowel and bladder function and developed an ascending, irreversible paraplegia. Infectious or neoplastic diseases of the spinal cord were ruled out. A magnetic resonance imaging scan of the spine resulted in a diagnosis of toxic myelitis. Previously observed cases of spinal neurotoxicity after cytarabine treatment are reviewed as well as current guidelines for the use of intrathecal chemotherapy in high-grade non-Hodgkin lymphoma. In summary, severe spinal neurotoxicity of intrathecal chemotherapy is a rare side-effect, however several studies suggest that the neurotoxicity of cytarabine is significantly enhanced by concurrent intrathecal and high-dose systemic administration. Simultaneous high-dose systemic and intrathecal chemotherapy with cytarabine should therefore be avoided.
