Review of clinical, cytogenetic, and molecular aspects of Ph-negative CML

Abstract Between 1985 and 1989, many cases of Philadelphia (Ph) chromosome negative chronic myelogenous leukemia (CML) were reported. For this review, the following selection criteria were used: the original articles on Ph-negative cases should provide clinical, hematologic, cytogenetic as well as molecular data. In addition, eight unpublished cases of Ph-negative CML are included that were studied in our institute during the last two years. Our purpose was to correlate presence or absence of the Ph rearrangement with the clinical features in an attempt to test whether the entity “Ph-negative CML” really exists and to identify the pathologic characteristics, frequency of occurrence, prognosis for survival, and underlying molecular mechanisms. Data on Ph-negative CML patients were compared with data on Ph-positive CML, atypical CML (aCML), and chronic myelomonocytic leukemia (CMMoL), reported in the same papers as the Ph negative patients. Essential for comparison of data from the different investigators appeared to be a clear description of criteria they used to establish the diagnosis CML, or alternatively a complete presentation of data for all patients reported in the articles. In most cases. Ph-negative CML was distinguishable from CMMoL and aCML, using simple criteria, e.g., differential count of peripheral blood and absence of dysplasia in the bone marrow. Cytogenetic analysis showed normal karyotype in most cases of Ph-negative CML. Interestingly, in cases with abnormal karyotype, chromosome 9 band q34 was relatively frequently involved in translocations with other chromosomes than chromosome 22, suggesting a variant Ph translocation not visible by cytogenetic techniques. This assumption was confirmed by molecular analysis, demonstrating bcr-abl rearrangement in 9 out of 10 of the latter cases. Results of cytogenetic and molecular investigations in 136 cases of Ph-negative CML reviewed in this article clearly indicated that molecular techniques are valuable tools for identification of bcr-abl rearrangements, indicative for the Ph translocation. The different mechanisms responsible for bcr-abl rearrangement in Ph-negative CML patients are discussed. The question remains whether all Ph-negative CML patients will have bcr-abl rearrangements, or whether alternative mechanisms will be identified that are responsible for this disease

The use of FISH with chromosome-specific repetitive DNA probes for the follow-up of leukemia patients

The use of fluorescence in situ hybridization (FISH) for the purpose of repeated follow-up examination of bone marrow samples from 38 leukemia patients was investigated. On the basis of conventional cytogenetic analysis, patients with acute leukemia whose leukemic cells carried numerical chromosomal aberrations were selected and followed with repetitive DNA probes that specifically hybridize to one chromosome type. Repeated cytogenetic metaphase analyses would have been laborious and not sensitive or quantitative enough to follow declining numbers of aberrant cells. FISH, as an interphase cytogenetic technique, provides a rapid and simple alternative with high sensitivity. Although FISH data before and after chemotherapy were in agreement with bone marrow cytology in 30 of 38 patients, discrepancies were noticed in specific cases. These could be explained by the presence of cytogenetically distinct subclones that behave differently during treatment, the presence of differentiated leukemic cells, changes in the chromosomal constitution caused by clonal relapse, or the fact that a numerical aberration is found by conventional chromosome banding analysis while the target region to which the probe is directed is still present in the nucleus as a diploid set

Phagocytic plasma cells in a patient with multiple myeloma

Phagocytosis of blood cells by malignant plasma cells in multiple myeloma is an extremely rare condition. Here we present a 39-year-old woman with multiple myeloma. Bone marrow smear showed an extensive phagocytosis of erythrocytes and platelets by myeloma cells

Cytogenetic findings in mouse multiple myeloma and Waldenström's macroglobulinemia

Multiple myeloma (MM) and Waldenström's macroglobulinemia-like lymphoma (MW) appear spontaneously in C57BL/KaLwRij mice at a frequency of 0.5% and 0.2%, respectively. They can readily be propagated by intravenous transfer of mainly bone marrow or spleen cells into syngeneic recipients. Previous studies demonstrated that these mouse malignant monoclonal gammopathies (MMG) show clinical and biologic features that closely resemble those of the corresponding human diseases and thus could be used as experimental models. We report on cytogenetic analysis of two mouse MW and five MM in vivo cell lines of the 5TMM series propagated in syngeneic mice. These studies demonstrated clonal abnormalities in all cell lines, hyperdiploid karyotype in both MW and one MM lines, and hypotriploidy, hypertriploidy, or hypotetraploidy in the other lines. Structural abnormalities of chromosome 15 were observed in all MM lines. In the five MM lines, frequent rearrangements were also found for chromosome numbers 1, 2, 5, and 12. A single chromosomal abnormality, as found in induced mouse plasmacytomas and resembling Burkitt lymphoma, was not found in mouse MM and MW. It was concluded that spontaneously originating C57BL MM of the 5T series is a better model for human MM than pristane-induced BALB/c or NZB plasmacytoma

The genes of freedom: Genome-wide insights into marronage, admixture and ethnogenesis in the Gulf of Guinea

The forced migration of millions of Africans during the Atlantic Slave Trade led to the emergence of new genetic and linguistic identities, thereby providing a unique opportunity to study the mechanisms giving rise to human biological and cultural variation. Here we focus on the archipelago of São Tomé and Príncipe in the Gulf of Guinea, which hosted one of the earliest plantation societies relying exclusively on slave labor. We analyze the genetic variation in 25 individuals from three communities who speak distinct creole languages (Forros, Principenses and Angolares), using genomic data from expanded exomes in combination with a contextual dataset from Europe and Africa, including newly generated data from 28 Bantu speakers from Angola. Our findings show that while all islanders display mixed contributions from the Gulf of Guinea and Angola, the Angolares are characterized by extreme genetic differentiation and inbreeding, consistent with an admixed maroon isolate. In line with a more prominent Bantu contribution to their creole language, we additionally found that a previously reported high-frequency Y-chromosome haplotype in the Angolares has a likely Angolan origin, suggesting that their genetic, linguistic and social characteristics were influenced by a small group of dominant men who achieved disproportionate reproductive success.1. Introduction 2. Materials and Methods 2.1. Population Samples 2.2. Expanded Exome Sequencing, Variant Calling and Quality Control 2.3. Population Structure Analyses 2.4. Genetic Diversity 2.5. Mitochondrial DNA and Y-Chromosome Variation 3. Results 3.1. Genetic Structure 3.2. Genetic Diversity 3.3. Reanalyzing previously generated uniparental Data 4. Discussio