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S Atwater

Publications and source records attributed to S Atwater.

8 recordsLinked to original sources
PubMed1998

The PEBP2betaMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia.

Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia. Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc). To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2betaSmmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2betaMYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2betaMYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2betaMYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.

Animals↗
PubMed1997

A PMLRARalpha transgene initiates murine acute promyelocytic leukemia.

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.

Animals↗
PubMed1996

Advances in leukocyte differential and peripheral blood stem cell enumeration.

Automated leukocyte differential counting has resulted in a marked improvement of the precision of leukocyte subclass enumeration. With advancement of this technology, algorithms have been developed to identify samples that require manual microscopic review. Complex flagging algorithms permit acceptable false-positive rates with effective use of microscopic review to identify significant morphologic abnormalities. Current literature indicates that the leukocyte differential is a poor case-finding index in both outpatient and inpatient populations. Development of highly automated technology has led to test over-utilization because of ease of performance despite recognized limitations in identifying clinically significant abnormalities. Enumeration of hematopoietic stem cells in harvested peripheral blood or bone marrow is critical for determining whether transplanted cells will produce adequate engraftment. Hematopoietic precursors express the CD34 antigen, are present as rare events in unmobilized blood, and are found in increased numbers after mobilization with chemotherapy with or without G-CSF. Flow cytometric detection of CD34+ cells is more rapid and precise than cell culture techniques and results are available in time to determine if further cell harvesting procedures will be necessary. CD34+ cell concentrations correlate with granulocyte-macrophage colony-forming unit counts as well as with time to engraftment. Although intralaboratory precision in measuring these infrequent events may be good, comparisons between different laboratories using aliquots of the same sample have yielded more variable results. Problems in determining precise and reproducible CD34+ cell concentrations may be due to nonspecific antibody binding, insufficient signal intensity of true positive events, differences in monoclonal antibodies and their fluorochrome conjugates, or failure of the total absolute leukocyte count to accurately reflect the population used for CD34 analysis.

Female↗
PubMed1995

Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia.

Leukemia may be viewed as a clonal expansion of blast cells; however, the role of primitive cells and/or stem cells in disease etiology and progression is unclear. We investigated stem cell involvement in leukemia using fluorescence in situ hybridization (FISH), immunofluorescence labeling of hematopoietic subpopulations, and flow cytometric analysis/sorting to discriminate and quantify cytogenetically aberrant stem cells in 12 acute myeloid leukemia (AML) and three myelodysplastic (MDS) specimens. Flow cytometric analysis and sorting were used to discriminate and collect a primitive subpopulation enriched in stem cells expressing CD34+ and lacking CD33 and CD38 (CD34+lin-). A subpopulation containing progenitors and differentiating myeloid cells expressed CD34, CD33, and CD38 (CD34+lin+). Nine specimens contained less than 10% CD34+ cells and, thus, were considered to be CD34- leukemias. Mature lymphoid, myeloid, and erythroid subpopulations were sorted on the basis of antigen-linked immunofluorescence. Cytogenetically aberrant cells in sorted subpopulations were identified using FISH with enumerator probes selected on the basis of diagnosis karyotype. Cytogenetically aberrant CD34+lin- cells were present at frequencies between 9% and 99% in all specimens. CD34+lin- cytogenetically aberrant cells comprised between 0.05% and 11.9% of the marrow/blood specimens. Cytogenetically aberrant CD34+lin+ cells constituted 0.01% tp 56% of the marrow/blood population. These data demonstrate that aberrant cells are present in primitive CD34+ stem cell compartments, even in CD34- leukemias. Stem cell involvement was confirmed further by sorting lymphoid and erythroid subpopulations from eight specimens in which the predominant leukemic population lacked lymphoid/erythroid differentiation markers. In these specimens, as well as in multiple lineages, suggests involvement of a cell(s) with multilineage capabilities. The ability of aberrant CD34+lin- stem cells to contribute to clonal and compartment expansion within immunofluorescently defined subpopulations was evaluated to explore the functional phenotype of aberrant CD34+lin- cells. Analysis of compartment size and aberrant cell frequency suggests that frequency of cytogenetically aberrant stem cells is uncoupled from compartment size. These data suggest that cytogenetically aberrant cells in the primitive compartment show varying abilities to expand primitive compartments. Cytogenetically aberrant CD34+lin- cells precede the blast subpopulation in hierarchical maturation and may in some cases by considered preleukemic, requiring maturation or additional mutations before transformation (eg, compartmental expansion) occurs.

ADP-ribosyl Cyclase↗
PubMed1990

Extranodal head and neck lymphoma. Prognosis and patterns of recurrence.

Stages I and II extranodal head and neck lymphomas treated between 1969 and 1986 were reviewed to determine prognosis and recurrence patterns. Forty-four patients had low-grade lymphoma, with 57% remaining disease free (median survival, 7.2 years). Radiotherapy provided long-term disease-free survival and palliation in the majority of patients. Relapse did not adversely affect survival. Eighty-eight patients had intermediate- or high-grade lymphoma, with 42% remaining disease free (median survival, 2.4 years). Treatment with radiotherapy alone was inadequate. Combined radiotherapy and anthracycline-containing chemotherapy appeared to be superior. Extranodal sites of first relapse were common. Central nervous system relapse was common with primary tumors located above the pterygopalatine line. Central nervous system staging and prophylactic therapy is warranted in patients with tumors above the pterygopalatine line.

Adult↗
PubMedDate not supplied

Congenital leukemia: successful treatment of a newborn with t(5;11)(q31;q23).

A male neonate presented with a high white cell count, an 11q23 translocation, and M5b leukemia. He was treated at 3 days of age with intensive combination chemotherapy after progressing despite exchange transfusions. The patient achieved complete remission at 28 days of age. Therapy was completed at the age of 6 months. At the time of this report, the patient is 17 months old and remains in remission. Twenty-nine patients with congenital acute myeloid leukemia were also reviewed. Twenty of these patients received varying therapies. Ten of the treated patients achieved complete remission; two died of toxicity; and eight died of progressive disease. Two patients had a translocation affecting 11q23. Congenital leukemia is a rare and usually fatal condition in patients without Down syndrome. The patient reported here shows that survival may be achieved with very intensive chemotherapy plus supportive care, despite extremely high white blood cell counts and unfavorable translocation.

Adult↗