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predominant cell type occurring either spontaneously or after therapy, while this appears to be more unusual in de novo ALL or ANLL (unpublished work). 111. Lympboproliferative Disorders Recent studies by DonIon et al. (1977), Kung et al. (1978), and ourselves (Mertelsmann et al. 1978b, 1979a) have demonstrated the clinieal significance of TdT determinations in patients with non-Hodgkin's lymphoma (Table 1). In patients with lymphoblastic lymphomas of the T and "null" cell type high levels ofTdT were observed as seen in ALL. Because a definitive histologie diagnosis is sometimes diffieult to make in this group of patients we have often found TdT determinations providing important diagnostic information. Lymphoproliferative diseases of the mature T and B cell type have been found to be TdT( - ) (Table 1). Although diffuse histiocytic lymphomas, whieh are diagnosed on the basis of the presence of large cells resembling histiocytes, generally represent B-cell proliferations, a few cases of "true" histiocytie lymphomas with cells exhibiting phagocytic properties and more recently lymphomas of the null cell type have been described which exhibited high levels of TdT in involved tissue (Gordon et al. 1978; Mertelsmann et al. 1978b). Although it is too early to determine the significance of these marker studies for the response to therapy and long-term prognosis in this group of patients, all patients with lymphoid neoplasias with high levels of TdT studied by us had a characteristic clinieal course resembling that of ALL. IV. TdT Determinations in tbe Monitoring of Disease Activity in TdT+ Neoplasia We have reported significantly elevated TdT levels in ALL bone marrow in complete remission on and off therapy as compared to normal controls (Mertelsmann et al. 1978b). The TdT levels characteristically fluctuated, whieh could not be explained by technical problems or chemotherapy. A preliminary analysis of our own data suggests an increased risk of relapse in patients with persistently elevated TdT values in eR. The clinical and biologic signifieance of elevated Td)' levels in ALL in patients in long-term remission off chemotherapy remains to be analyzed; if indicative of residual disease, this observation would be important for the understanding of the pathophysiology of leukemias and for the design of therapeutic strategies. E. Conclusion From our own studies and work by published others it appears that determination of TdT activity and definition of cell phenotypes in hematopoietie malignancies are useful tools for the classifieation of these disorders and have signifieant prognostic, c1inieal, and pathogenetie implications. Although several questions still remain unsolved, this comprehensive approach, when correlated with c1inical presentation and conventional morphology, might help the physician by providing objective diagnostic criteria for prognostic subgroups unidentifiable by conventional methods. Furthermore, this approach will help to understand the underlying pathogenetic processes leading to the clinieal syndromes of human leukemias and lymphomas. Acknowledgments The skillful technical assistance of Ms. Loma Barnett und Ms. Sa An Hu is greatly appreciated. We would like to thank Ms. Cynthia Garcia for typing the manuscript. References (Representative references were selected, which list further literature regarding specific aspects of TdT.) - Bollum FJ (1979) Terminal deoxynucIeotidyl transferase as a hematopoietic cell marker. Blood 54: 1203-1215 - DonIon JA, Jaffe ES, Braylon Re (1977) Terminal deoxynucIeotidyl transferase activity in malignant lymphomas. N Engl J Med 297: 461-464 - Gordon SD, Hutton JJ, Smalley RV, Meyer ML, Vogler WR (1978) Terminal deoxynucIeotidyl transferase (TdT), cytochemistry, and membrane receptors in adult acute leukemia. Blood 52:1079-1088 - Incefy GS, Mertelsmann R, Yata K, Dardenne M, Bach JF, Good RA (1980) Induction of differentiation in human marrow T -cell percursors by the synthetic serum thymic factor, FTS. Clin Exp Immunol 40:396-406 - Janossy G, Bollum FJ, Bradstock KF, McMichael A, Rapson N, Greaves MF (1979) Terminal transferase-positive 71
human bone marrow cells exhibit the antigenic phenotype of common acute lymphoblastic leukemia. J Immunol 124: 1525-1529 - Janossy G, Hoffbrand AV, Greaves MF, Ganeshaguru K, Pain C, Bradstock KF, Prentice HG, Kay HEM, Lister TA (1980) Terminal transferase enzyme assay and immunological membrane markers in the diagnosis of leukaemia: a multiparameter analysis of 300 cases. Br J HematoI44:221-234 - Kung PC, Long JC, McCaffrey RP, Ratlif RL, Harrison TA, Baltimore D (1978) Terminal deoxynucleotidyl transferase in the diagnosis of leukemia and malignant lymphoma. Am J Med 64:788-794 - Mertelsmann R, Koziner B, Ralph P, Filippa D, McKenzie S, Arlin ZA, Gee TS, Moore MAS, Clarkson BD (1978a) Evidence for distinct lymphocytic and monocytic populations in a patient with terminal transfer ase positive acute leukemia. Blood 51: 1051-1056 - Mertelsmann R, Mertelsmann I, Koziner B, Moore MAS, Clarkson BD (1978b) Improved biochemical assay for terminal deoxynucleotidyl transferase in human blood cells: Results in 89 adult patients with lymphoid leukemias and malignant lymphomas in leukemic phase. Leuk Res 2:57-69 - Mertelsmann R, Koziner B, Filippa DA, Grossbard E, Incefy G, Moore MAS, Clarkson BD (1979a) Clinical significance of TdT, cell surface markers and CFU-c in 297 patients with hematopoietic neoplasias. In: Neth R, Gallo RC, Hofschneider P-H, Mannweiler K (eds), <strong>Modern</strong> trends in human leukemia In, Springer, BerIin Heidelberg New York p 131 - Mertelsmann R, Moore MAS, Clarkson BD (1979b) Sequential marrow culture studies and terminal deoxynuc1eotidyl transferase activities in myelodysplastic syndromes. In: Schmalzl R, Hellriegel KP (ed) Preleukemia, Springer, BerIin Heidelberg New York, p 106 - Mertelsmann R, Gillis S, Moore MAS, Koziner B (1981) Abnormal TCGF response pattern in human leukemias exhibiting high TdT activity. In: Moore, MAS (ed) Differentation factors in cancer, Raven Press, New York - Modak MJ, Mertelsmann R, Koziner B, Pahwa R, Moore MAS, Clarkson BD, Good RA (1980) A micromethod for determination of terminal deoxynuc1eotidyl transferase (TdT) in the diagnostic evaluation of acute leukemias. Cancer Res Clin Oncol 98:91-104 - Sarin PS, Anderson PN, Gallo RC (1976) Terminal deoxynucleotidyl transferase activities in human blood leukocytes and lymphoblast cell lines: High levels in lymphoblast cell lines and in blast cells of some patients with chronic myelogenous leukemia in acute phase. Blood 47:11-20 - Silverstone AE, Cantor H, Goldstein G, Baltimore D (1976) Terminal deoxynuc1eotidyl transferase is found in prothymocytes. J Exp Med 144:543-548 - Steinmann G, Mertelsmann R, de Harven E, Moore MAS (1981) Ultrastructural demonstration of terminal deoxynuc1eotidyl transferase (TdT). Blood 57:368-371- Vogler LB, Crist WM, Bockman DE, PearI ER, Lawton AR, Cooper MD (1978) Pre-B cellleukemia. Anew phenotype of childhood lymphoblastic leukemia. N Engl J Med 298:872-878 72
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Haematology and Blood Transfusion 2
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Dr. Rolf Neth, Universitäts-Kinder
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Participants of the Meeting Aaronso
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Kurth, R, Friedrich-Miescher-Labora
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Wilsede Scholarship Holders (Grante
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Preface Gut ist eine Lehrart, wo ma
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Personal and scientific discussion
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Acknowledgement We should like to t
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Wilsede, June 21 1978 Memorial Trib
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limiting benign lymphoproliferative
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this most unlikely, however (for re
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longer subject to the same control
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Bregula U, Wiener F, Harris H (1971
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fresh lymph node biopsies from ten
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Fig. 3. Binucleate mitosis in an ob
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y Fig. 4. Schematic diagram of post
Page 33 and 34: than that among patients with Stage
Page 35 and 36: Tests of binding affinity, agglutin
Page 37 and 38: N Engl J Med 297: 963-968 - Green I
Page 39 and 40: Clinical Aspects
Page 41 and 42: "ring chromosome". "Mar" is marker,
Page 43 and 44: 191 chromosomally abnormal patients
Page 45 and 46: tumors of both African and non-Afri
Page 47 and 48: Haematology and Blood Transfusion V
Page 49 and 50: Retrospective group 26/93 evolved l
Page 53 and 54: Treatment
Page 55 and 56: advantage in terms of duration of f
Page 57 and 58: leukaemia. An analysis of 168 patie
Page 59 and 60: 11. Treatment Program Chemotherapy
Page 61 and 62: efractory congestive heart failure
Page 63 and 64: period (Sequence II) was gene rally
Page 65 and 66: children with a multiple drug proto
Page 67 and 68: DAYS 1 5 10 15 20 25 30 35 , I I I
Page 69 and 70: Biologically Drug Outcome fit" sens
Page 71 and 72: may counterbalance the potential be
Page 73 and 74: Ht (0--0) 50 40 30 20 10 0 Platelet
Page 75 and 76: 10 7 ,-----------------------------
Page 77 and 78: 11. Haematological and Biochemical
Page 79 and 80: 0\ 0\ INTERFERON ... 10 3 rl E "'
Page 83: ("pre-B" phenotype) has been descri
Page 87 and 88: 10 9.,0 MBKCC .. .,4 B prot:oool 1'
Page 89 and 90: demann W, Büehner T, Arlin Z, Gee
Page 91 and 92: -...l 00 a-tLDRENS CAt«:ER S TU>Y
Page 93 and 94: prognostic characteristics under in
Page 95 and 96: significantly higher in HR} (14.5%,
Page 97 and 98: normal or elevated immunoglobulin l
Page 99 and 100: References Andreeff M, Darzynkiewic
Page 101 and 102: R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
Page 103 and 104: Table 3. Influence of initial featu
Page 105 and 106: LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
Page 109 and 110: me nt indicated that additional the
Page 111 and 112: 42:2123-2134 - Chessells JM, Cornbl
Page 113 and 114: Baum et al. 1979). This study was b
Page 115 and 116: 1. 0 '--'1--" 0.9 e: o .- VI VI E C
Page 117 and 118: e: o e: 1. 0 ,.--...-- 1'"'\ ......
Page 119 and 120: In conclusion, we can state that th
Page 121 and 122: Haematology and Blood Transfnsion V
Page 123 and 124: INDUCTION VCR + PRED + ASNASE (wk 3
Page 125 and 126: SCHED.INT 1 MTX • ! Adria MTX •
Page 127 and 128: ~ looh---------ooooc>----o---c>----
Page 129 and 130: Consoll- Irra .tlon t) .tlon Indu
Page 131 and 132: Highrisk Standard risk Table 1. Cli
Page 133 and 134: Cumulo/ive comp/el9 remission 1.0 .
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10° 8 = 6 ö 4 Non T Cell .~ :ö
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Haematology and Blood Transfusion V
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% SURVIVAL 100 ~ ~II 0 80 60 40 - -
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a) Percentage of donor cell mitoses
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Table 5. Results of bone marrow tra
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...... w N Table 7. Clinical result
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agent had to be added and that in t
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C. Chronic Myelogenous Leukemia The
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Patients with a suitable donor rece
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No. Recurrent Leukaemia Other death
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followed by dialysis against isoton
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HS, HL- Heme >_ 40 0 HS I ;:. =====
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knowing at present. These genes may
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esistance to antifolates. In Vitro
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a DNA probe specific for the gene t
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translocation between chromosomes 9
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Table 1. Subdivision of 1827 Myelo-
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NORMAL CELL ®
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some change of the primary type, in
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F. Transformation of Mouse Bone Mar
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were carried out with 3H-MTX in the
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the lysozyme cDNA prepared from ovi
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et al. 1976). The BJAB cellline in
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dalton bands corresponding to light
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1979). The EBV-carrying cell lines
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producer lines (DAUDI and P3HR-1),
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G, Giovanella B, Westman A, Stehlin
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Dc;bt CT + i J.I9 Raji; 1. i .. 100
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c. Discussion During infectious mon
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C. Nonepisomal Viral DNA We have us
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A 260 3.0 A B 1670 70 N2 2.0 c: E .
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vivo. Nature 260:302-306 - Kirk JTO
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Fig. 1. a Polyacrylamide gelelectro
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1979). The lymphocyte subpopulation
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lysin 0 antigens are found, and mix
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Pope JH (1978) Long-term T cell-med
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Haematology and Blood Transfnsion V
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Charaeteristie Morphologie maturati
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after TPA-induction (Table 3). The
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PA (1978) Reactivity of a rabbit an
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Blood Monocyte. B lood Monocytes 1-
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and nonhistone proteins can serve a
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The findings of the evaluation of s
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Fig. 3. Tumor grawth of L 428 cells
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Cell biological and Immunological A
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consideration. Sanel (1973) obtaine
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endotoxin serum, were used. A parti
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monocytic leukemia cell line in cul
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B. Isolation, Characterization and
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don al hemopathies generally displa
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nitors. Blood Cells 6:595-607 - Min
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\I) ....I ....I IU Jl 200 r 100 90
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their haemopoietic cells' ability t
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normal normal ALL ALL ALL persons p
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64.5 { V)
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References Biermann E, Neth R, Gros
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ehambers, the growth pattern observ
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References Anderssen LC, 10kinen M,
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REH CELL UNE TO CALLb~Ö ~q~ V.M. c
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the macrophage series in which the
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Table 1. Production of factor depen
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Table 1. Characteristics of the adh
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Fig. 3. A human marrow culture at 6
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300 250 • HYPERPROLIFERATIVE PATT
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Fig. 9. Nonadherent population from
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The cobblestone areas were often no
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L (1976) Induction of colony format
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B. Materials and Methods J. Tissue
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Fig. 2. Ultrastructural appearance
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Table 1. Monoclonal antibody reacti
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al. 1979; Janossy et al. 1979) is e
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to which this is an exact replica o
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inger JL (1976) Distribution of la-
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I region antigens were found to be
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have been reported to be present on
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V. FunctionalAssays Assays for PHA
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Functional studies of UCHT1 separat
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40 ,...... (5 L.. C o u 30 .9 ~ .~
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with immunohistochemieal methods (L
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can be dissected by cloning. Utiliz
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Table 1. Origin and marker profile
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complete identity of gp 100 from no
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Table 1. Reaction of single anti se
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media. Following 24-h incubation, c
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nonleukemic eells (Greaves 1979). L
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Fig. 2. Cytocentrifuged smears of b
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Modification of amino-groups of hum
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disturb this balance in the directi
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The majority of human blood lymphoc
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of the EBV infected B cells. Howeve
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and immunoglobulins. J Immunol 120:
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" K 10 • j ~ ALL RNlL AL wtfh les
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tion akuter Leukämiezellen in "spo
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D. Results and Discussion J. Acute
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selectively responsive to different
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l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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Table 2. Growth inhibition of S49 e
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Reverse Infectious ASC/2X1Q6 transc
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munized animals to 1316 tumor cells
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Haematology and Blood Transfnsion V
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Fig. 3. Expression of retroviral gp
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pg70. J Exp Med 143: 151-166 - McGr
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Table 1. Expression of tumor antige
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Virological and Molecularbiological
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Table 1. Oncogenic properties of re
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also Fig. 1). It followed that the
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whether this sequence is related to
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zed in infected cells argue that th
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a specific viral transforming prote
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detect viral RNA as the only charac
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Eisen H (1980) Myeloproliferate vir
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p,60- -34K - 1 2 3 4 Fig. 1. In vit
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.. p - • a'T ... I .t'l Fig. 4. D
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Fig. 2. Photomicrographs of NY68 in
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DEAE (o(lJmn 'liI GI -2 2 o e s 1
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vity was deterrnined. For endogenou
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pr 180 - - - P 12/15 - A B c D E F
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85,- 66- -27 - -66 40- 27- -1'9 19-
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= 0.5 o E Q. o ILI 0.4 (J) « ILI .
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Table 1. Oncogenic potential of avi
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100 III GI c: o "8 80 > w
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Expt. No. Infecting virus Proportio
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Haematology and Blood 'fransfusion
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sequences, provided its gag portion
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77:3009-3013 - Hu SSF, Moscoviei C,
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RI 2.2 md and Hind III 2.6 md leuke
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RELATIONSHIP OF ENDOGENOUS AND EXOG
Page 445 and 446:
E ........ E Cl. U E :::l .... Q) (
Page 447 and 448:
References Astrin S (1978) Endogeno
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the same animal were examined (e.g.
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I) 'IQ a \0 - CL -- Fig. 2. Restrie
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~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
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Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
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Haematology and Blood 'fiansfusion
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Osteopetrosis and osteosarcomas occ
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Lymphoma cellline Table 1. T and B
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Table 2. In vivo growth and oneogen
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Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
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- Shoemaker C, Goff S, Gilboa E, Pa
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indieate a shifting of target eell
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Table 2. Expression of Jl and Sourc
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
Page 487 and 488:
Mak TW (1979) Proc Natl Acad Sci US
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Table 1. Transformation of 3T3 cell
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inserts in the genome of rapidly tr
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pulations, it seemed likely that th
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contains antigens which react with
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le of reacting in sensitive radioim
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gic approach. In: Hiatt HH, Watson
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12 Eco R [ Fig. 1. Hybridization pa
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
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cultures. These cells did not conta
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indication of malignant T-cells in
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Fig. 3. Thin-section electron micro
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Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
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specific signals into nonspecific s
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Table 2. Distribution of HTLV-relat
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u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
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SSV TrS-gp labeled effectively with
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
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Antisera a Table 1. Immunofluoresce
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Haematology and Blood 'ftansfusion
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y competition RIA yielded virtually
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SiS'V' gp70: ANTIGEN, ANTI BODY, IM
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type-C virus p30 antigen in cells f
Page 547 and 548:
c. Results The fractionated whole-b
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induced antibodies as well as exper
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- Fig. la-f. Retravirus particles p
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eplication of infecting murine leuk
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immunodeficiency, multic10nal lymph
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Bovine leukemia --, proteins of 499
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Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
Page 565 and 566:
Haematology andBlood Transfusion Su
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