I am taking the opportunity of adding a few words to what has already
been laid about the role of chromosomal changes in the occurrence of leukaemia.
Very briedy it can be stated that we have three kinds of indication.
A. Association of mongolism with leukaemia
Even before mongolism was recognized as being determined by a trisomy,
the correlation between this congenital disease and acute leukaemia had been
The analysis of Stewart and Hewitt (1959) shows that mongols are
possibly twenty times more frequently leukaemic then normal children.
The nature of this leukaemia of mongols is also very special for in 37
cases, Stewart (1961) reports 21 blast-cell, and 16 acute lymphoblastic cases.
The conclusion of Stewart being that these leukaemias are confined to one type
only: the stem-cell type.
B. Association between chronic myeloid leukaemia and
partial deletion of a small acrocentric
The discovery of Nowell and Hungerford (1960) that there were two
populations of cells, one entirely normal, the other containing cells
exhibiting a very small, acrocentric, chromosome has been repeatedly confirmed
for chronic myeloid leukaemia.
The published data are summarized in Table I.
Hence in 28 cases the small chromosome, called Ph1 was observed. This
can hardly be considered as a pure coincidence.
The nature of the Ph1 is not definitely established but it is most
likely that it is a normal small acrocentric (21 or 22) which has lost more
than half of its long arms.
C. Association between acute myeloblastic leukaemia and
deletion of a small acrocentric
To my personal knowledge 4 cases have now been reported. One by
Hungerford (1961) with 6 cells with 45 chromosomes (without determination of
the lost one) among 61 examined; 1 by Fortune et al. (1962) exhibiting a clone
with a quite small Ph1 chromosome; 2 (Ruffie and Lejeune, 1962) exhibiting a
clone of 45 with the loss of one of the small acrocentrics.
|Author||Number of cases||Number of cases with
Ph1||Remarks on negatives cases
|Nowell and Hungerford, 1961||10||9||1
examined in remission
|Tough et aL, 1961||18||13||3 are of very
mild evolution, and 2 of these are probably radio-induced, the 2 others were
tested in the terminal acute phase
|Ohno et al., 1961||5||5||
|Fitzgerald, 1962||2||1||1 possibly
Taken together we have the actual correlation: Congénital trisomy for
a small acro-centric mongolism Stem-cell leukaemia X 20 Clonal partial deletion
of (22-21) (Pu1) partial or total deletion of (21-22) chrome granulocytic
leukaemia (28 cases on 35 studied) acute myeloblastic (3 cases on 3 studied)
|Congenital||trisomy for a small
acrocentric||mongolism Stem-cell leukaemia X 20
|Clonal||partial deletion of (22-21) (Ph1) partial or
total deletion of (21-22)||chronic granulocytic leukaemia (28 cases on
35 studied) acute myeloblastic (3 cases on 3 studied)
This simple comparison excludes a chance effect and leads to the
hypothesis that the same acrocentric is involved in all cases, namely the 21.
It must be emphasized that this identification agrees with the microscopic
observation and also with the abnormality of the nuclei of granulocytes known
in mongols since 1947 (Turpin and Bernyer).
A very simple conclusion drawn from these data could be as follows:
there are on chromosome 21 genes or blocks of genes which normally depress the
granulocytic series. Triplication of these increases the reactivity of the
lymphatic series, and conversely, loss of them permits abnormal growth of the
Those reflections are, for the moment, purely theoretical, and the
number of observations on which they are based is much too small. Nevertheless,
it can reasonably be hoped that in the near future, accumulation of data will
allow a judgment on the role of chromosomal aberrations in the production of
MOLE: I would draw the opposite conclusion. If, in fact each leukaemia
is in any sense unique, then you wouldn't expect the chromosomes to be the
same. I would expect that something that was aetiologically important should in
fact be different in each leukaemic line so that the fact that each individual
leukaemia appears to be unique karyotypically seems to me to be sensible. That
doesn't obviate your objection - a perfectly real one that all the chromosomal
changes could be epiphenomenal. But I think it's wrong to expect that one
should get a consistent change. Recent evidence confirms that the Philadelphia
chromosome is not in fact a consistent finding in chronic myeloid leukaemia.
Last week the Edinburgh people reported two cases of ankylosing spondylitics
with chronic myeloid leukaemia without the Philadelphia chromosome in either of
them. One could perhaps say that if the Philadelphia chromosome was a
consistent finding in chronic myeloid leukaemia, this would be evidence that
chronic myeloid leukaemia was not itself neoplastic. It only became neoplastic
with the acute myeloid transformation with which it so often terminates, and
then you do get karyotypic multiformity.
KOLLER: Each case must really be judged on its own. I consider that to
make such a sweeping statement as "every leukaemia arises from a chromosomal
abnormality" is quite illogical.
ILBERY: May I resolve this apparent conflict? Does it matter if there
are cells with a mode greater than 40 present? Surely the point is that there
are abnormal cells present at all. Cells with greater chromosome numbers can't
be without influence on adjacent normal cells.
ALEXANDER: I have been working with a murine leukaemia which was
originally produced by Law many years ago and carried in tissue culture
subsequently for 5 or 6 years. Single cells are sufficient for transplantation
of this tumour. Clones can be originated in tissue culture from single cells
and thus one can start off with a genetically pure line. Dr. Davies has looked
at these for us and he tells us that they are strictly diploid-I think
something like 90% diploid in spite of the fact that they've been in tissue
culture for so many years. We now have a number of mutants with different
characteristics, e.g. different radiosensitivities, yet they have still 40
chromosomes. Certainly Prof. Koller's conclusion that one cannot say that
leukaemia is invariably associated with changes in chromosome number seems to
be very well exemplified here.
LAMERTON: May I ask whether with trisomics you have much variation in
the morphology of one or more of the chromosomes? If you dont, it's a bit
difficult to see why you only get the leukaemia in a few of the cases. In the
trisomies, do the three 21's look the same always?
LEJEUNE: Yes they are. There is no detectable change in the karyotype
of bone-marrow or blood.
LAMERTON: You don't get any variation, and yet you still only get an
increase in the leukaemia by a factor of 10. Many people who have those three
apparently identical chromosomes don't get leukaemia.
LEJEUNE: That is not so simple, because we don't know at all whether
they get it or not. When we are dealing with the mongols, we have to say that
we are dealing with a new populationbecause they are now allowed to live their
lives with antibiotics but previously they were dying much earlier. We have a
small proportion of leukaemia which was 20 times higher Chan in the normal
population, but they have been at risk for a relatively short period. It is not
known, but likely that mongols will possibly get a lot more leukaemia, when
they reach 20 or 30 years old, which is quite unobserved at the moment.
LAMERTON: Is not this figure of twenty times very misleading?
LEJEUNE: It is very misleading. Rougbly it compares 6-year-old
children-mongols-with the normal 6-year-old populationthat does not give an
estimate of the general risk during the whole life-time.
UPTON: I've been very much interested in discussing this problem with
P. R. J. Burch who is spending a year at Oak Ridge. I think it's his belief
that the Philadelphia chromosome arts merely as the equivalent to mutations in
two loci. He visualizes that one must have homologous loci on both chromosomes,
in other words a four-hit situation for chronic myelogenous leukaemia. With the
Philadelphia chromosome you have two to four hits.
ALEXANDER: Dr. Lejeune, you had 2 cases of these acute leukaemias.
Does this mean that only 2 cases have ever been looked at?
LEJEUNE: So far as I know, for acute myeloblastic leukaemia; yes, just
last week a third one was published; in that case there was quite a big
deletion of the 21, not a complote disappearance.
KEPES: What is the frequency of this chromosome anomaly?
LEJEUNE: In both cases there are 2 populations of cells in these
individuals. One is entirely normal, and the other shows the abnormality. In
the cases we have checked there was one boy and one girl-the girl died too
early, but we could also do the skin of the boy-to show that ho has quite
normal cells of the skin. As to the frequency of the abnormal cells it is of
the order of one-half or more-but the actual numbers are possibly greatly
disturbed by differential survival in vitro.
BINGELLI: Have you clone any electron microscopy on this problem?
LEJEUNE: Electron microscopy of human chromosomes is technically very
difficult. They are too big and too thick.
BINGELLI: I thought you might have done serial sections.
LEJEUNE: Yes, but when you do that you are on a very different scale
so you do not know what you are seeing. The only published attempt has given an
enlargement which is not greater than that obtained with the optical
microscope; so the electron microscope; for the moment is of no use at all. The
only way in our opinion is for the cytogeneticists to become as intelligent as
Drosophila and to become able to produce polytene chromosomes in vitro.
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