Mice with hematopoiesis deficient in glycosyl phosphatidylinositol (GPI) linked molecules: A possible model for paroxysmal nocturnal hemoglobinuria(PNH)

M. Bessler, V. Rosti, G. Tremml, Vera Soares, Pier Paolo Pandolfi, Lucio Luzzatto

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In every patient with PNH a proportion of Mood cells is deficient in all GPI anchored proteins due to a somatic mutation which has occnned in the X-tinked PIG-A gene in a bematopoiea'c stem cell. In order to create a mouse model for this disease we have inactivated by homologous recombination the pig-a gene in mouse embryonic stem (ES)-cells and studied the contribution of pig-a null ES-ceUs to bematopoiesis in chimerk mice. Blood chimerism was determined using monoclonal antibodies towards GPI-linked surface antigens; CD24 for red cells, Gr-1 for myeknd cells and CD48 for lymphocytes. We found that pig-a null ES cells can contribute substantially to fetal erythropoiesis, with up to 36% of red ecus being CD24-negative at day 17 p.c.. By contrast. at 1 day afterbirth me percentage of CD24-negative red cells did not exceed 10%. and at the age of three months they were hardly delectable. Because of the very low neutrophil count we could not prove conclusively that there was a significant contribution of pig-a null cells to myelopoiesis. Lymphocytes deficient in CD48 were only observed in I out of the 7 mice in which we had documented contribution of pig-a null cells to erythropoiesis. In this mouse 1.8% of Tlymphocytes and 0.4% of B-lymphocytes were CD48 deficient and these values were stable over the observation period of 3 months. In order to obtain only CD48 deficient T- aid B- lymphocytes we injected our pig-a null ES-ceUs into bla&tocysts from RAG-1 null mice, in which me development of B- and T- cell lineages is arrested at an early stage. In the chineras we obtained, all B- and T- lymphocytes were negative for CD48. Our data show that pig-a null ES-cells can contribute to hematopoiesis and can undergo erytbroid and rymphoid differentiation. Analysis of pig-a null chtmeric mice will provide further insights into the functional role of GPI-linked surface molecules in hematopoiesis and in die immune system. In contrast to what is seen in patients with PNH, pig-a activation in normal mice does not per se provide the bematopoietk stem cell with a proitferative advantage, suggesting dut in PNH patients some additional, possibly environmental factorfs) may be needed for die expansion of the mutant clone.

Original languageEnglish
Pages (from-to)1062
Number of pages1
JournalExperimental Hematology
Issue number9
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation


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