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Haematology and Blood Transfusion Vol. 26 <strong>Modern</strong> Trends in Human Leukemia IV Edited by Neth, Gallo, Graf, Mannweiler, Winkler © Springer-Verlag Berlin Heidelberg 1981 The Different Origin 01 Primary and Secondary Chromosome Aberrations in Cancer G. Levan and F. Mitelman A. Abstract We have proposed a hypothetical model to explain the role of chromosomal aberrations in malignant development. In this model we postulate two kinds of chromosomal changes: (1) primary, active changes caused by direct inter action between the oncogenic agent and the hereditary material of the host cello These changes are mainly somatic mutations, but mayaIso be associated with directed structural changes visible in the microscope; and (2) secondary, passive changes arising randomly by nondisjunction and structural rearrangements. They are followed by selection of cells with changes that amplify the primary change and thus appear as nonrandom chromosome patterns. This hypo thesis is discussed in the light of 1827 cases of human malignancy in which we have recently surveyed and systematized chromosomal aberrations. Special support for the idea of somatic mutations as the initiator of malignant development comes from work of Knudson and collaborators in human retinoblastoma. The Phl chromosome, predominant during the chronic phase of chronic myeloid leukemia (CML), is proposed as an instance of a primary change, whereas the chromosome changes during the blastic crisis of CML will illustrate the secondary changes. The most common of these secondary changes is actually the doubling of the Phl and thus an amplification of the primary change. The increase in number of copies of a specific chromosome reported by Green and collaborators demonstrates that this kind of amplification can result in direct response to the need for a specific gene located in that chromosome. B. Introduction Towards the end of the nineteenth century it became known from the work of pathologists that malignant cells were often liable to chromo so me aberrations. Boveri in 1914 hypothesized that these aberrations actually were the cause of the malignant growth. At that time, technical difficulties in the study of mammalian chromosomes effectively put a stop to any thorough investigation of chromosome aberrations in tumors. Improvements in methodology in the early 1950s made detailed studies feasible, but only after the introduction of chromosome banding in the early 1970s could chromosomal and subchromosomal changes in tumor materials be analyzed with great precision. The results from both experimental and human tumors were significant: c1ear nonrandom patterns of aberrations became discernible. There were, however, considerable difficulties in interpreting the findings. Firstly, there were usually many different types of changes even within a clinicaHy weH defined group of tumors. Secondly, there was a variable degree of "background noise", i.e., chromosome changes that did not fall into the nonrandom pattern. Thirdly, there were cases of malignant tumors in which even refined chromosome banding did not reveal any aberrations. C. Chromosome Aberrations in Human Malignancies We have attempted to collect data as completely as possible from all human tumors that have been studied carefully by chromosome banding techniques. The bulk of the material 160
Table 1. Subdivision of 1827 Myelo- Chronic myeloid leukemia (CML) cases of human neoplasms proliferative t(9 ;22) and other aberrations 361 with chromosome aberrations disorders Aberrant translocations 94 identified by banding techni- Acute myeloid leukemia (AML) 496 ques Polycythemia vera (PV) 86 Myelodyscrasia (MD) 278 Lympho- Malignant lymphomas (ML) 105 proliferative Burkitt's lymphoma (BL) 24 disorders Acute lymphocytic leukemia (ALL) 156 Chronic lymphocytic leukemia (CLL) 30 Monoc1onal gammopathies (MG) 23 Solid Benign mesenchymal tumors (BMT) 56 tumors Benign epithelial tumors (BET) Carcinomas (CA) Malignant melanomas (MM) Neurogenic tumors (NT) Sarcomas (SA) 9 87 8 7 7 comes from the published cases in the literature. In addition, there are unpublished cases from our own laboratory and from other laboratories, the latter kindly made available by the original investigators. All in all we have collected and systematized 1827 cases of human malignancies exhibiting chromosome aberrations. This figure does not inc1ude about 2000 cases of chronic myeloid leukemia that have the Ph1-translocation as the only aberration. According to the diagnoses the material has been subdivided into 15 c1asses (Table 1). The aberrations of each patient with a parti- cular disease may be scored and surveyed in histograms such as the one in Fig. 1. This diagram represents 496 cases of acute myeloid leukemia. We think it must be obvious to all that the various chromosome types are affected by aberrations in a nonrandom fashion. Clearly chromosomes Nos. 7, 8, 17, and 21 are selectively involved in aberrations.1t should be noted, however, that the nonrandom elevation of the aberrations in these chromosomes is blurred by the random aberrations occasionally affecting all chromosomes and causing the rather high background level of aberrations. 40 % 30 20+------ 10 -1-.....,..-- o 1 3 5 7 9 11 13 15 17 19 21 X 2 4 6 8 10 12 14 16 18 20 22 Y Chromosome No. Fig. 1. Histogram of per cent aberrations affecting the 24 human chromosome types in 496 patients with acute myeloid leukemia 161
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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
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than that among patients with Stage
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Tests of binding affinity, agglutin
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N Engl J Med 297: 963-968 - Green I
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Clinical Aspects
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"ring chromosome". "Mar" is marker,
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191 chromosomally abnormal patients
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tumors of both African and non-Afri
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Haematology and Blood Transfusion V
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Retrospective group 26/93 evolved l
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Treatment
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advantage in terms of duration of f
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leukaemia. An analysis of 168 patie
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11. Treatment Program Chemotherapy
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efractory congestive heart failure
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period (Sequence II) was gene rally
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children with a multiple drug proto
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DAYS 1 5 10 15 20 25 30 35 , I I I
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Biologically Drug Outcome fit" sens
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may counterbalance the potential be
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Ht (0--0) 50 40 30 20 10 0 Platelet
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10 7 ,-----------------------------
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11. Haematological and Biochemical
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0\ 0\ INTERFERON ... 10 3 rl E "'
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("pre-B" phenotype) has been descri
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human bone marrow cells exhibit the
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10 9.,0 MBKCC .. .,4 B prot:oool 1'
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demann W, Büehner T, Arlin Z, Gee
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-...l 00 a-tLDRENS CAt«:ER S TU>Y
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prognostic characteristics under in
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significantly higher in HR} (14.5%,
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normal or elevated immunoglobulin l
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References Andreeff M, Darzynkiewic
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R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
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Table 3. Influence of initial featu
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LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
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me nt indicated that additional the
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42:2123-2134 - Chessells JM, Cornbl
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Baum et al. 1979). This study was b
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1. 0 '--'1--" 0.9 e: o .- VI VI E C
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e: o e: 1. 0 ,.--...-- 1'"'\ ......
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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 .
Page 135 and 136: 10° 8 = 6 ö 4 Non T Cell .~ :ö
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Page 139 and 140: % SURVIVAL 100 ~ ~II 0 80 60 40 - -
Page 141 and 142: a) Percentage of donor cell mitoses
Page 143 and 144: Table 5. Results of bone marrow tra
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Page 165 and 166: knowing at present. These genes may
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Page 181 and 182: F. Transformation of Mouse Bone Mar
Page 185 and 186: were carried out with 3H-MTX in the
Page 189 and 190: the lysozyme cDNA prepared from ovi
Page 193 and 194: et al. 1976). The BJAB cellline in
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Page 197 and 198: 1979). The EBV-carrying cell lines
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Page 201 and 202: G, Giovanella B, Westman A, Stehlin
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Page 207 and 208: c. Discussion During infectious mon
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Page 215 and 216: vivo. Nature 260:302-306 - Kirk JTO
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Page 221 and 222: 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
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E ........ E Cl. U E :::l .... Q) (
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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
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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
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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
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RNA -, of tumor virus 439 Rous sarc
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Haematology andBlood Transfusion Su
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