Spontaneous remission in monosomy 7 myelodysplastic syndrome.
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Chromosomes, Human, Pair 7↗
Biomedical subjects
L C Moscinski
Publications and source records attributed to L C Moscinski.
Immunoglobulin germline mu transcripts in acute myelogenous leukemia cells vary in splicing pattern and are heterogeneous.
Germline transcription of the immunoglobulin (Ig) locus is felt to play an important role in B cell differentiation. Similar transcripts are also found in neoplastic myeloid cells, but are of unknown significance. We have mapped these RNAs using reverse transcriptase polymerase chain reaction amplification. Unlike B cell transcripts, the majority of myeloid mu transcripts do not contain amplifiable enhancer sequence or complete 5' sequence. The extent of this deletion is related to the degree of myeloid maturation, with transcripts in the most primitive myeloid cells more closely resembling those in B cells. Variable 3'-splicing patterns are also observed in myeloid cells, unlike the single pattern identified in early B cells. Using primers which span the region from the 3' end of C mu 4 to the 5' end of the second membrane exon (M2), the splice sites between C mu 4 and M1, and between M1 and M2 have been analyzed. Our data suggest that factors important in initiation of germline mu transcription are present in both B lymphoid and myeloid cells, but that lineage-specific modifying factors alter this expression during myeloid maturation. Thus, the finding of Ig transcripts and other evidence of B lymphoid differentiation in acute myelogenous leukemia most likely reflects a retained common hematopoietic gene program.
B-Lymphocytes↗
High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma.
Interleukin-6 (IL-6) is a multifunctional cytokine postulated to play a central role as a growth factor for multiple myeloma (MM). We evaluated the spontaneous secretion of IL-6 in supernatants of Ficoll-Hypaque--enriched bone marrow (BM) cultures from 35 patients with MM. The levels of IL-6 were correlated with biological and clinical characteristics of the disease. High levels of IL-6 production defined a subgroup of patients with low tumor burden as determined by lower serum beta 2-microglobulin (B2M) (P = .02) and lower percentage of myeloma cells infiltrating the bone marrow (P = .003), higher synthetic rates of monoclonal protein (P = .006), and low proliferative compartments as measured by the percentage of Ki-67--positive myeloma cells. Patients with high proliferative fractions (Ki-67--positive myeloma cells > 20%) had significantly lower levels of IL-6 when compared with patients with low proliferative fractions (P = .005). Our findings do not support IL-6 as a major growth factor for MM, but demonstrate an association of high levels of IL-6 secretion with low tumor cell burden and low proliferative fraction.
Aged↗
Sterile transcription of immunoglobulin/T-cell receptor genes and other evidence of early lymphoid differentiation in acute myelogenous leukemia.
Acute leukemia can show evidence of mixed lineage differentiation, with both myeloid and lymphoid features. To correlate phenotypic lymphoid differentiation with gene rearrangement and transcription of these loci, we examined 50 acute leukemias (including those with both myeloid and/or lymphoid phenotypes) and four non-hematologic controls. We analyzed rearrangement at the immunoglobulin (Ig) and T-cell receptor (TCR) loci, gene expression at these same loci (T beta, C mu, JH), as well as expression of components known to be involved in the process of rearrangement (RAG-1 and terminal deoxynucleotidyl transferase, TdT). In the majority of acute leukemias, including those with myeloid phenotypes, we demonstrated events characteristic of early lymphoid differentiation. We observed that expression of TdT mRNA and sterile transcription at both the Ig and TCR loci (transcription without gene rearrangement) was unexpectedly common in both acute biphenotypic leukemia and acute myelogenous leukemia (AML), and occurred in the absence of phenotypic lymphoid differentiation. Furthermore, coordinated transcription of JH and T beta was frequently noted in the presence of C mu. RAG-1 was detected in approximately 50% of leukemias studied, but expression correlated inversely with TdT and did not correlate with sterile transcription or gene rearrangement. The pattern of sterile transcripts in lymphoid and neoplastic primitive myeloid cells supports the concept of a common early gene program.
Adolescent↗
The significance of an elevated serum lysozyme value in acute myelogenous leukemia with eosinophilia.
According to criteria established by the French-American-British (FAB) classification, a diagnosis of acute myelomonoblastic leukemia (FAB M4) is based on the presence of 20% bone marrow monocytes or a serum lysozyme level that exceeds the reference value by three times. Reported here is a case of acute myelogenous leukemia with eosinophilia and a cytogenetic inversion of chromosome 16 (inv 16) that lacks morphologic, cytochemical, and immunophenotypic features of monocytic differentiation, but which is associated with an elevated serum lysozyme value. The authors used an immunoelectron microscope to localize lysozyme to both normal and abnormal eosinophil granules, in addition to the secondary granules of myeloid precursors and monocytes. This enzyme could not be demonstrated within the myeloblasts of the patient studied. Postfixation with osmium tetroxide greatly reduced the staining intensity within the crystalloids of normal eosinophils, but only minimally affected that of monocytes, neutrophils, normal eosinophil granule matrix, and the abnormal granules of the leukemic eosinophils. These results demonstrate that lysozyme is present in both normal and leukemic eosinophils and that elevation of serum lysozyme in patients with acute myelogenous leukemia with eosinophilia is not a reliable indicator of monocytic differentiation. Furthermore, an occasional case of acute leukemia with inv 16 is classifiable as acute myelogenous leukemia with differentiation (FAB M2).
Adult↗
Acute myelogenous leukemia in the elderly.
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Aged↗
Pure red cell aplasia: treatment with intravenous immunoglobulin concentrate.
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Adrenal Cortex Hormones↗
Surface marker analysis and karyotype distinguish acute biphenotypic leukemia from acute myelogenous leukemia expressing terminal deoxynucleotidyl transferase.
Surface phenotyping by flow cytometry and cytochemical study were used to identify 15 adult patients with acute leukemia displaying ambiguous phenotypes. Differences were found in the blast cell karyotype and immunoglobulin gene rearrangements of terminal deoxynucleotidyl transferase (TdT)-positive acute myelogenous leukemia (AML) and biphenotypic leukemia expressing B lymphoid and myeloid markers. The karyotypic abnormalities, t(9;22) and t(4;11), were noticed in acute biphenotypic leukemia, and were consistently associated with rearrangement at the immunoglobulin locus. Furthermore, coexpression of CD19/CD20 and either myeloperoxidase or myeloid surface markers were predictive of finding the t(9;22) or t(4;11) karyotype. Patients with TdT-positive AML, on the other hand, were less likely to show rearrangement at the immunoglobulin locus, and did not have the t(9;22) or t(4;11). Instead, a variety of nonrandom karyotypic abnormalities were seen, including trisomy 13. Unlike common AML, the majority of TdT-positive cases demonstrated an abnormal karyotype with duplications and/or deletions present in all cases. In no instance was trisomy 8, t(8;21), t(15;17), or any other isolated translocation identified. The authors therefore suggest that immunophenotyping, when combined with cytochemical analysis of TdT and myeloperoxidase or Sudan black B, may aid in the characterization of subgroups of atypical acute leukemia, such that alternate approaches to therapy can be evaluated.
Antigens, Neoplasm↗
A case of the eosinophilia-myalgia syndrome associated with use of an L-tryptophan product.
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Eosinophilia↗
Identification of a series of differentiation-associated gene sequences from GM-CSF stimulated bone marrow.
The production of terminally differentiated granulocytes and monocytes occurs by a program of orderly and sequential gene expression. This genetic program can be studied in vitro utilizing granulocyte-monocyte colony stimulating factor (GM-CSF) to stimulate proliferation and myeloid cell maturation. We have identified a series of genes expressed during early myeloid differentiation by differential screening of a cDNA library prepared from GM-CSF stimulated murine progenitor cells. From 72 potential early myeloid specific clones, three (B9, C9, C15) were characterized further. The time course of RNA accumulation during GM-CSF stimulated maturation demonstrated a unique pattern for each clone. B9 was expressed predominantly on day 3, and followed a pattern of accumulation similar to that for myeloperoxidase. (Jaffe et al. (1988), Oncogene, 2, 167-174). C9 expression increased gradually to a maximum level on day 3 and then plateaued; it appeared to be equally expressed in granulocytes and monocytes. C15 was expressed at a consistently high level in unstimulated cells and at 1-3 days post GM-CSF stimulation. It then decreased to undetectable levels. Hybridization of these clones to a panel of murine tissue RNAs demonstrated restricted expression of B9 to bone marrow, while C9 was present in most murine tissues, including thymus. C15 expression was relatively restricted to ovary/uterus, liver and adrenal, in addition to bone marrow. Partial DNA sequence analysis suggested that B9 was a novel sequence not previously identified. C9 was identified as thymosin beta-4, and C15 showed extensive homology to lactotransferrin. Thus, screening a bone marrow cDNA library by differential hybridization has successfully yielded a series of DNA sequences regulated during murine myelopoiesis. These include novel sequences (B9), genes previously known to be regulated during myelopoiesis (C15), as well as sequences not recognized previously as being associated with myeloid differentiation (C9).
Animals↗
Myeloperoxidase-positive acute megakaryoblastic leukemia.
Acute megakaryoblastic leukemia (FABM7) is an unusual but well recognized form of acute myelogenous leukemia in which the bone marrow blast cells are phenotypically recognized by the demonstration of cytoplasmic platelet peroxidase or surface staining for the IIb/IIIa platelet-specific glycoprotein. Herein, the authors report a case of acute megakaryoblastic leukemia that satisfies the accepted French-American-British criteria and in which the blast cells also exhibit evidence of myeloid differentiation, including surface MY7 (CD13) by flow cytometry and immunocytochemical positivity for myeloperoxidase. These findings suggest that megakaryoblasts may be closely related to myelomonoblasts, that they have the potential to partially differentiate along multiple phenotypic lines, and that aberrant phenotypes can occur that do not correspond to known stages of normal maturation. The authors illustrate the difficulty in classification of these aberrant phenotypes by standard cytochemical and morphologic criteria.
Cell Membrane↗
Myeloperoxidase and oncogene expression in GM-CSF induced bone marrow differentiation.
DNA synthesis, morphology, specific RNA accumulation and rates of specific protein synthesis in GM-CSF stimulated bone marrow progenitor cells were studied. DNA synthesis increased markedly for 64 hours and then gradually decreased to 5% maximal activity by 160 hours. Morphologic examination 40 to 64 hours after stimulation revealed an increasing proportion of immature myeloid cells. After this proliferative peak, cells differentiated into segmented neutrophils and monocytes/macrophages; only mature forms were present by 160 hours. Accumulation of mRNA for c-myb and c-myc was maximal at 40 hours just prior to maximal [3H]thymidine incorporation, while maximal accumulation of histone type 3 (H3) was coincident with maximal [3H]thymidine incorporation at 64 hours. As proliferation decreased and differentiation proceeded, levels of mRNA for c-myb and H3 decreased markedly, while levels of RNA for c-myc decreased gradually and remained elevated above day 0 levels. Levels of c-fos mRNA fluctuated slightly during the first 64 hours of culture and increased 13-fold by 160 hours when mature cells were present. Similarly, beta-2 microglobulin mRNA increased steadily to maximal levels at 112 to 160 hours which were 15-fold higher than day 0 levels. Myeloperoxidase (MPO) mRNA was present in maximal amounts at 40 to 64 hours after stimulation with GM-CSF as the number of immature myeloid cells peaked. Immunoprecipitation of MPO from pulse-labeled cell lysates demonstrated a 7-fold rise in synthetic rate of MPO of 64 hours and a 28-fold decline by 160 hours when only 5% immature myeloid cells were present. Thus, MPO protein synthesis closely follows MPO mRNA accumulation. Immunoprecipitation of lactoferrin, a marker of myeloid secondary granules, demonstrated a gradual 5-fold increase in synthetic rate as the cells matured. Taken together, these data show that maximal expression of the early myeloid differentiation enzyme myeloperoxidase in GM-CSF stimulated normal bone marrow cells occurs during peak proliferation of immature myeloid cells.
Animals↗
Pancytopenia in propionic acidemia: hematologic evaluation and studies of hematopoiesis in vitro.
This study investigated the hematologic abnormalities of an infant with propionic acidemia and reversible pancytopenia. Light and electron microscopy of her bone marrow revealed severely disturbed cellular morphology with trilineage dysmyelopoiesis, hemophagocytosis, and numerous multinucleated histiocytes and megakaryocytes. The effects of her serum and of organic acids associated with propionic acidemia were studied on hematopoiesis in vitro. Mouse erythroid (CFU-E) and granulocyte-monocyte colonies (CFU-GM) were assayed by fibrin clot technique; human CFU-GM were grown in agar culture. The infant's serum reduced mouse CFU-E and CFU-GM by 43 and 32%, respectively, compared with normal human sera, but had no effect on human CFU-GM in our culture system. Buffered propionic acid caused concentration-dependent inhibition of mouse CFU-E and human CFU-GM over a range reported in sera of acutely ill infants with propionic acidemia. Neither cell viability nor subsequent colony formation was diminished by preincubation of bone marrow cells with propionic acid for 48 h. The three other organic acids studied, tiglic acid, 3-OH propionate, and glycine, did not inhibit growth of mouse CFU-E, CFU-GM, or human CFU-GM, and glycine significantly enhanced formation of the latter. Evaluation of the infant's hematologic abnormalities suggests that inhibition of bone marrow proliferation and maturation and, perhaps, shortened red blood cell survival were responsible for her pancytopenia. The studies performed in vitro implicate propionic acid in this hematopoietic dysfunction.
Amino Acid Metabolism, Inborn Errors↗
Primary eosinophilic granuloma of frontal lobe. Diagnostic use of S-100 protein.
Solitary eosinophilic granuloma of the frontal lobe of the brain is a rare lesion. A 30-year-old Jordanian man with a history of recurrent bilateral chronic middle ear infections and tuberculosis presented with focal seizures. A solitary right frontotemporal mass was diagnosed by brain biopsy as an eosinophilic granuloma. Immunoperoxidase stains of virtually all histiocytes in the lesion were strongly positive for S-100. Four cases of eosinophilic granuloma and one of Letterer-Siwe disease were also examined, and virtually all histiocytes demonstrated strong S-100 positivity. In comparison, 24 reactive or infectious granulomas were examined for S-100 staining and most showed complete negativity of histiocytes in granulomas for S-100. This is the first report in the literature that has examined the results of S-100 staining in a large number of reactive or infectious granulomas and compared it with S-100 staining in eosinophilic granuloma. This report illustrates that S-100 can be useful in distinguishing eosinophilic granuloma, generally considered to be part of the larger group of histiocytic disorders known as histiocytosis X, from reactive or infectious granulomatous conditions of similar or confusing histology.
Adult↗
Acute lymphocytic leukemia (ALL) in elderly patients.
OBJECTIVE: To compare the clinical and biologic characteristics, response to therapy and outcome of adult patients with ALL above and below the age of 55. DESIGN: Retrospective review of clinical and laboratory data. SETTING: University affiliated Cancer Center and Veteran's Hospital. PATIENTS: Thirty-three newly diagnosed, consecutive, adults with ALL seen over a nine-year period. RESULTS: while no differences were demonstrated in the distribution of recognized prognostic indicators (such as cytogenetic abnormalities or immunophenotype), individuals over the age of 55 had significantly lower remission rates and shorter survivals. CONCLUSIONS: The outcome of elderly patients with ALL is very poor. This is primarily related to an increase in the number of early deaths during induction, as well as a higher prevalence of disease refractory to standard chemotherapy programmes. There is a need for new treatment protocols designed for the elderly ALL patient, as well as a better understanding of the unique biological characteristics of the disease in this age group.
Adolescent↗
Recent progress in multiple myeloma.
Multiple myeloma is recognized as a neoplasm of phenotypically mature plasma cells which produces a variety of clinical symptoms related both to tumour infiltration of the bone marrow and cytokine production. The latter results in bone disease and a complex interactive network between plasma cells, marrow stromal cells and other hematopoietic cells. This serves to sustain the myeloma proliferative pool and promote maturation and secretion of monoclonal immunoglobulin. Whereas the recognizable tumour cells in myeloma are the most mature B cells, early lymphoid cells are involved in the disease and probably represent the proliferative pre-plasma cell compartment. The definition of the myeloma 'stem cell' remains controversial, but our understanding of early pre-plasma cell differentiation in multiple myeloma has been aided by studies on normal non-neoplastic equivalents. Techniques like high resolution flow cytometry, flow cytometric DNA analysis and improvements in our ability to obtain karyotypic data in multiple myeloma will improve our understanding of myeloma cell biology, hopefully yielding new prognostic information. Finally, improvements in assessing prognosis will help identify patients whose survival with standard therapy is limited and who may require innovative or aggressive treatment protocols. These individuals must be separated from patients who either require no initial therapy or who are likely to have good outcomes with standard approaches.
Antigens, Surface↗
Thymosin beta 4 synergizes with human granulocyte-macrophage colony-stimulating factor in maintaining bone marrow proliferation.
Recent evidence supports a role for thymosin beta 4 (T beta 4) in the inhibition of murine hematopoietic stem cell proliferation. This supposition results from studies in which the N-terminal tetrapeptide derived from native T beta 4 was administered to mice and appeared to prevent CFU-S recruitment into DNA synthesis. The importance of this observation was the concomitant ability of the tetrapeptide to prevent cytosine arabinoside (ara-C) toxicity in mice given LD50 doses of this drug. In the present study, we have extended these observations by demonstrating that whole synthetic T beta 4 is more effective than the N-terminal tetrapeptide in protecting mice from the toxicity of ara-C. This observation supports the hypothesis that T beta 4 is the biologically important parent molecule for this activity. To determine if inhibition of cell cycle progression also occurs in committed human bone marrow progenitors treated with T beta 4, we have investigated the effects of synthetic T beta 4 on proliferating and unstimulated enriched human bone marrow. In short-term liquid cultures studied sequentially over 1-7 days, T beta 4 failed to inhibit cell proliferation, but maintained the proliferative effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on days following maximum stimulation (days 5-7). No effect was noted before the fifth day in culture, nor did T beta 4 exert any demonstrable effect in the absence of added GM-CSF. Any observable effect of T beta 4 required that it be present in the cultures on or before day 3 of GM-CSF stimulation. These results suggest that an additional effect of T beta 4 is the stimulation of a subpopulation of committed human bone marrow precursor cells to become more sensitive to the growth-promoting activity of GM-CSF, thereby enhancing myelopoiesis. It is of interest that the N-terminal peptide of T beta 4 is a shared sequence with tumor necrosis factor alpha, which is also known to have a similar stimulatory capacity. We, therefore, postulate that the growth enhancement noted in short-term cultures is mediated by the region containing these shared sequences.
Animals↗
CD44 expression and MMP-2 secretion by mouse glioma cells: effect of interferon and anti-CD44 antibody.
We have previously reported that invasiveness of mouse glioma G-26, which expresses CD44 adhesion molecule, was inhibited in vitro following treatment with anti-CD44 antibody or mouse interferon alpha/beta (MuIFN alpha/beta). Here, we evaluated whether the expression of transmembrane CD44 adhesion molecule and/or secretion of extracellular matrix metalloproteinases (MMPs) were affected when glioma cell invasion was inhibited. Flow cytometric evaluation of CD44 adhesion molecule expression in G-26 glioma using anti-CD44 antibody, confirmed that G-26 cells were CD44+. Following 3-day treatment with MuIFN alpha/beta at 8 x 10(2) or 8 x 10(3) IU/ml of glioma cells, the expression of CD44 was not significantly affected as reflected by CD44+ cell number and fluorescence intensity. The pretreatment of glioma cells for 1 day with anti-CD44 antibody resulted in a 30-60% decrease of CD44 expression. This coincided with significantly (p < 0.05) lower cell activity as judged by MTT assay for mitochondrial activity. The zymographic evaluation of MMP activity in the G-26 glioma cell culture showed a high level of the active form of MMP-2. This level of MMP-2 was decreased following 3 day treatment of G-26 glioma cells with either 8 x 10(2) or 8 x 10(3) IU/ml of MuIFN alpha/beta but only the latter concentration produced statistically significant 55% decrease. However, following a 1 day treatment of G-26 glioma cells with anti-CD44 antibody, the level of active MMP-2 form was not significantly affected. These findings indicate that while the inhibitory effect of IFN on glioma invasion was accompanied by a decreased level of the active form of MMP-2 released extracellularly, the expression of the transmembrane CD44 adhesion molecule was not affected. Conversely, anti-CD44 antibody pretreatment of G-26 glioma, which led to the inhibition of glioma invasion, resulted in decreased CD44 expression and lower cell activity but had no effect on the MMP-2.
Animals↗