The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis by Stephen E. Straus, Elaine S. Jaffe, Jennifer M. Puck, Janet K. Dale, Keith B. Elkon, Angela Rösen-Wolff, Anke M. J. Peters, Michael C. Sneller, Claire W. Hallahan, Jin Wang, Roxanne E. Fischer, Christine M. Jackson, Albert Y. Lin, Caroline Bäumler, Elke Siegert, Alexander Marx, Akshay K. Vaishnaw, Tamara Grodzicky, Thomas A. Fleisher, and Michael J. Lenardo Blood Volume 98(1):194-200 July 1, 2001 ©2001 by American Society of Hematology

Structure of the TNFRSF6 (APT1) gene encoding the Fas protein, showing locations of the mutations associated with ALPS and lymphoma.Exon 9 is expanded to show α-helical regions of the intracellular death domain.67 Mutations are newly described or previously... Structure of the TNFRSF6 (APT1) gene encoding the Fas protein, showing locations of the mutations associated with ALPS and lymphoma.Exon 9 is expanded to show α-helical regions of the intracellular death domain.67 Mutations are newly described or previously reported from NIH (indicated by black symbols),8 11 15 44 Cornell University, New York (indicated by gray symbols),10 26 or Dresden, Germany (indicated by white symbols).30 Mutations seen in individuals with lymphoma are indicated by boxed symbols. Stephen E. Straus et al. Blood 2001;98:194-200 ©2001 by American Society of Hematology

Histopathology and immunopathology of lymphomas in ALPS patients Histopathology and immunopathology of lymphomas in ALPS patients.(A) T-cell and histiocyte-rich B-cell lymphoma diagnosed in patient 3-II-3. Histopathology and immunopathology of lymphomas in ALPS patients.(A) T-cell and histiocyte-rich B-cell lymphoma diagnosed in patient 3-II-3. Large polylobated tumor cells, which stained for CD20, are seen in a background of T lymphocytes and histiocytes. (B-D) Nodular lymphocyte-predominant Hodgkin disease diagnosed in patient 3-II-1. (B) A rim of epithelioid granulomas surrounds a large nodule containing neoplastic cells. (C) A single polylobated L&H cell is identified in a background of small lymphocytes. (D) A CD20+ L&H cell is rosetted by a rim of CD20− T cells. Numerous CD20+ small B cells are present in the background. (E) Burkitt lymphoma presenting as an omental mass in patient 26-II-4. Tumor cells are moderate in size with clumped chromatin and basophilic nucleoli. A prominent starry sky is present. (F) Tumor cells uniformly express CD20. The growth fraction was 100% with MIB-1 (Ki-67) staining. Identical histologic and immunophenotypic features were seen in lymphoma involving small bowel in patient 30-III-2. (G) An unusual form of follicular lymphoma was diagnosed in patient 55-II-1. Neoplastic cells surround hyalinized and possibly regressed follicular remnants. (H) CD20 immunohistochemistry emphasized follicular pattern. (I) The neoplastic cells are moderate in size with clumped chromatin. (J) A follicle-center origin for tumor cells is supported by Bcl-6 immunohistochemistry, which selectively stains the neoplastic cells within the follicles. Original magnification (A), ×400; (B), ×60; (C), ×400; (D), ×400; (E), ×400; (F), ×400; (G), ×200; (H), ×200; (I), ×400; and (J), ×250. Stephen E. Straus et al. Blood 2001;98:194-200 ©2001 by American Society of Hematology

Resistance of lymphoma cells to Fas-induced apoptosis Resistance of lymphoma cells to Fas-induced apoptosis.Cell suspensions prepared from a lymphomatous lymph node from NIH ALPS proband 55 were subjected to apoptosis induction either via antibody cross-linking of Fas or by 5 μg/mL staurosporine that induces a... Resistance of lymphoma cells to Fas-induced apoptosis.Cell suspensions prepared from a lymphomatous lymph node from NIH ALPS proband 55 were subjected to apoptosis induction either via antibody cross-linking of Fas or by 5 μg/mL staurosporine that induces apoptosis by the mitochondrial pathway. The percentages of cells dying are compared with the results with resting lymph node (RLN) cells from patient 55, with cells from a family 17 ALPS patient, with Jurkat T-lymphoma cells, with KK124B Burkitt lymphoma cells, and with normal human tonsil cells. Flow cytometry analysis showed that lymphoma cells from patient 55 were of large size and exhibited B-cell markers and that both the lymphoma cells and the smaller resting lymphocytes expressed normal levels of the Fas receptor on the cell surface. Stephen E. Straus et al. Blood 2001;98:194-200 ©2001 by American Society of Hematology