1(!73-197h
Janice )'forgan
INTFWDn~TION
J fo
'c7l j E~~
I
'J?A-
atterrrt tn identi.fy one particular cause of leuke-
'T\)
,Zi-j
. (vltT r! i
R?VIE~v
and L TTERATUR"S
a by study';rf' severa]
patients over a period of one year
an apnreciation for the
H~wever,
D'lr1her
~ R.r~:e
"'1r i ahl es +hat exis:, in
.jf'
Play h'? gained.
T,e'lke!T'is ~ S
:--1
:..:rouD of disorders in 1,.T':1ich "rY>ol
tiJm, mat11ra.t i on, And release ()f
",!~+-~in
vpnt.
c()nt;ro 1
1
hound:'! hy nnrrnsl
Leukw'":~R,
."
a" rr:a1'1t:i tat:
,·.1p11
r"'ce ,T0:1
i
such arc analysis
leuko~yt8q
physio10:,::5~8.l
Hhi~h lIay
j
fer8-
i.s no lancer
P')PchBnisms of
produce qualitative
8?
if'- Hh~ t'e blood r'<'11 s, has
attpntion as R killer of 1'1an in the
"han.~es
"P
('nr:~:;jr1pr··)1;1('
Many theories
~ave
heen nrcposed
8S
But i.n the 19st
far, only chrnnic granu-
~hus
locytic leukemiA has
~een
assoc~ated
with a
na~tiG~lRr
chroMosoma' qlteratior--that hei~g the ~hilad~lphi8 rhro~08 0 )1]e. 2 The rema;ninc tYres of 1 euker'de havE' yet to he
Therf:oso~al
3bnor~ali~ies
]")0,11 Yemori 0.1
!-I('s~,; t.8~
Cancer is an
rells
rf severRl
leukemia patients ot the
•
irrpve~s~hlp
process,
that is, 2ancer
n:)t trar:sforrr: baC'K to normal cells.
C13"
fTlherpf'",.,p
f'aneor ~lght bf' a
"]1']01ecu18"
~iolosir81
disease, i.e., one invnlvtng ahnormal genetics
af'-d further t.hat the nrncess is continued as a kinrl T..,
,. . .,. 'It''.
~.~"
nn.• If]
'-"
m
'n
f 01] 1"
~ 'J ~~
(' ell s,
1)
An
..,
of'
tl.-t •
..
:!8 gene,',"c
np!G1!:
n,f' '"'81"C8r
"'0'1"-'+
f' ; >
."",,0
r '" ~ t s 1! flY P
1-,
C
p:J
h yD nth e s .; zed •
cell:" cont.ain ::'anrF"Y' genAs, Lp., genes
w"1.pr; r-:x-orr":;Si?d Ca 11se cal1r.er.
In no'1-
",J~;'"'h
'"'ancer ('011s these
8ene~
aY'e
re~",p.ssed.
P-;thP,r bt an eaY'!V '""'tai'"p eH' fol101oJinp; snme t'Toe
of viral or othAn" i~fe~tjon, lYR0fe~; (~o~nl~~p
('1" oarti a1)
')~elJ1"S as a res1Jl t' of ~ which "~~n~er
r:en;'"," or :'3rowth 3e:>8S th.at are ncr'TIs-j 1 y ~,""tirms
of viral eAnnm~Q ~e~o~~ i~~nrnnrR~ed into +~p
~Rn~er cell
zennmo ~:>d ar 0 expressed, re32n~'o~~
of' whet"her nther viral ,Ctpnes ape f:tnctioD"'l.
I:ancer resuJts f'rom one'>0Y' mere "samat1,:' r:Jtations".
C::>Dcer rp~'11"':8 f'rol'l epigeneti r> (non-gene \:hanses
in cells. f
"the
Ko'-ler,
fa~~
~hat 1)
C"ign~fl(>anr.e
()f
r>:.itot,i,"" o;soY'r1e"'s lies "n the
they indicate the metabolJc instability
('ells which are easjJy affected by E'mvironmenta',
+,1J'TIOY'
f3rtnrs Rnd ?' thP.7 represent th.e
ulAr
in
~f
h.etero~enejty
t:UrrlO
n
hy which cell-
is introduced, maintained, and increased
c~everaJ. mitotic mal funetio:Js ha'.''''
tissues. liS
cation May he nhsprv?d
~on-disjunctjon,
-8~hinery
~n
8n~e
nells.
and lagging.
is nrobahly the most ::;.:-)mmon
Fragment~tior
~1!rnm0S0mG
anomal y observed in ca!lcer')us t j s ~ue.
ape scattered throughout the cell.
disintecrate in the
a
~e~trcmere
~ytonlasm
and consequently
The i'ragmen t s usually
berause they dn nnt p8ssess
ranno~
move to opposite poles
at anaphase, thus resulting in their not being incorponated
in
t~e
daughteY> nnC'lei at telophase.
Dicentric chr')mnsnmes are the result of breaks in two
chromosomes followed hy the hpoken narts being joined in
a nel'<l aprangement that p"'8ults in a single ch n nrl"SOp1f' with
two eentromeres.
Kolle~
Thf' rS"'1aining ends forP1 acentric fragments.
" b e~ween
+
states that .,"1 f' t'oe regIon
the two c~ntromeres
is very short, the dicentric chromosome can be incorporated
into one nucleus,
~n
wh~ch
case it will appear
agai~
at
the next mit8sis."A
s eviden~'ed hy the c"':romosomes~l umping
at metaphpse.
"St:L cki'C'ess"
tog~ther
sni!ldle.
ments.
j
~~)y)ea~
-
88
frB£!'-~
"
results in one daughter
cell containing more chromJneSB,
"
oso~es than norma] and another containing fewer.
The :rrsgular distribution of chro]",10s::JP'leS into severa:L
~uc1ei
:Ls b~":'--l[;ht Rbout by
,~:ultir)nlar rrj+:i:.t','-
u
s'~indle.
The nuclei tend to be d~f~8rent sizes and are often held
Ce11~
tosethe':-> by bridgps.
with tHO diRtinct nuclei have
a conpl'3te cell mpmbrane f0rming retHcen da;lghter cells.
But Hhe'1 the
''''ont8.~n
nucl'~i
div~,de
,~
11"
[';:1
chromosom~s
mix.
Repet5t:ion of' the
an_t" cells with hundreds of ('hro:nop~ocess
The above malfunctions in the mitotic
possible causps oP
Cells nOH
~hr0:'10S0mes.
the Ll-:2. nU::1ber of
proeeS8 results ,J,..,:.
the
t~e
are
chromosomal aberrations that exist
'-:1 lellkeY>1ia patie-:1ts.
MATERIALS and METHODS
The present study of chromosomes was conducted on
peripheral blood and bene marrOH sBY>1ples of leukemia patients
Standard leukocyte and bone
marrOH pr0C'C'dures
l1~pd.
"]>.0;-->8
'9re;ared 1--ltd ch in turn are
After cuI turin?:, s1 ides were
a~alyzed
s('anning for abnornaJ:i ties Has
ehr:J'Ylosome COlU-:t.
Visual
done using a light
Y>1i~roscopp
~ells
~ere
and photographs of unusual
prepared.
CJ-:romo SOJ1'le tech..Yli q1Je :
chased tn
to establ i sh ~ modal
one hundred ml
:r:edi:Je js pipetted in
5
Chr"omo some eul ture medi UP:. pur-
bottles fY>om GIl3CO Has used.
ml
aljq,--~ot8
i.nto sterile sereH cap
tubes t:,nd the tubes are taped shut. rjlhi s
,~aintaj-:1
a
dr~~
T'H.
However,::
~
'J'hi s
thp med'.:lrl
i~s
j
s
imT'Ol~t8nt
to
rh"Y uran thawIng,
or two of .01 N HCl will return it to its original
yelJ0wi sh ('olnr, which indicates the
rro~)er :1H.)
The
A sample ·,)f fonr nr fi ve ml of' D8Pipheral bJ,ood or
heme n:nrr01-l is drawn in a
hepR.rani~ed
tubE'.
'J'wo c'ulture
":,11oes are set up fro[r; this sample b:; dr01'P:ing fouY'')>"> five
f1ry,'" of 1tJhole bJ God into the medium.
After the blood is placed lnto the tubes of medium,
t~1e
tubes are
slapte(~
~
n the incub!1tor for sevent;,' two
I
I
_
8ince it is diffi-
tr.ar ahovp the
o~t i~lJ-,"
thi rty seVAn degrees.
At the pnd of SPVR'1t:T hv n
hOllrs t.he cell s are har"fested
frlJowinz a ~0diri~ati~'1 or the Rhode Island Hospital Methnd.
1. Add 0.c:':,,1 rO'1(''''ntratcd ("ol~hir>:inA to eD(~h vial 1}~
hour hpi'ore harve f' ti nr;, to rreven t
for:".a t i on of the sp j ndT e
fibers.
a ~ i n e 1> Y
~
i pet t e an d mj x •
?•
Add
3.
Sp~n
It.
Evacuate t.he tube down almost to the
with
th~
different natients.
-I-~n:-'
a)10
~llspend
~~nu~9s
c:' ",.1
0
f
N
8
1'1 centrifuge at 900 rpm's for 10 Minutes.
('el~s
1,yj
and then sain at
S.
Adele:; ml hypotonic KCl
th the p:pette.
pnn rpm's
Lea'Ie for
as rossihlp to
nui~kly
~11
(o)1e
pa~t
~ln0ja1
Beatie
tubes so
S ml of
~.
t~8t
rll
ftx8tivA end centpifuge.
~
t~mes.
Air dY'Y.
~Stain
~s
kept at ~7
For staining slides GiemsA stain is used.
beo 1,:sed (lr ?to('k Gierr!s!l
hy p~acing one via'
st~lin
~owdpred ~~A~S8
tn d~ss()Jv8 :In a vUltpr hAth
/'ddl:S ml
gives a
.n00S% colchicine.
KCl hyp0tonic sohlti0~1 13 .07SV and
deSY'oes ~8nt~gY'ade in the in~ubBt0r.
r1a~T
~~
Repeat two
"Hake one slide from each eulture.
dilution of .1 Ml
the
to three ~a~~s 2nn
the cpl} s ~Pl'ied:! 8 tt"1 y,
Th~s
st'ljr
f·:>l:~
a('~0
-::ro,'"' e",:;han(1) to the +uhp ancl r'lix
6.
solu-
rop 10 minutes.
Add.
Add 3 to
uSlng
Evacua te ::'!o\-'m to the bottoPl (i t i s important to
do this as
fixn~ivo
botto~
(S[-~-f,O
or Dcetnre-frpo q~cC''1oJ
Co:rr1(>Y'cial
mRY be prepared
(0.5 em)
~nto
a~
de:=rees for 1\-:·-
and st0re in.
al~ber
?
h0urs).
l'nttle.
24
rll C" f '/J~ tr? r
rll !1h()ST)h8t'" h:lffcY' '?tnF (,.J.
J.
~ .... ~
<
:
Phn:v-hat,0 buf'feY' (10%)
(1 Mr"
K~{~P04
?6. r::' 1:;1 ~{/H?()ll
(1 H)
+ ,\ Yj ~j 6. j, VI j t h 1 N K OR.
\
73.5 mJ
A "': ~ '.1 S t
rli .... (·,~ ..· ~:rt('i3ET.c.,t~r cXRJ11ination of ti ssu:::s, +:~p
,..~·1~ st·, ),,, stud1ed "'lust be dividinG ranjdly"1:; thE'
t~~V:e ~,f <""!"'~"'~~,;: ir:.r;.
T~ ~Oyr;t~ cHses,
c:el'l d:i.sT)!~x")~~r;Yi
cr?ates "l nrr)h 1 PY'1 "_ f' -the; 1-; C!SI.1(' :: s densr'.
II ":-nY't
T;lrr>
term ('eJ 1
j}-:'P11bRtion ~Yl3.~T be em01nyGo 1) tr)
~~'-~~0.3S0
ths nunb 0 Y' r.~ dividinc cells Rnd 2) to allow ~j~0 fn~
a. ;: 5.:l 1J ~ +~
~~ j ':? ~ !'l ( , O f fer t •
~i (; 1~J e yT C' r ,
R :J ::! ). ~ ~ 1h f-l ti r)y; st,--:-' iCl:'(''''t''''d bph"een obtainins ti-)(' t.l ssu,' aWl
Y}"-)
~xar1in1':,"~"~
... '"
t})(~
n
,....
'~~'l~0r:~)S(Y~''1e~)
ra~sP8
t~A
2·r~tj(',is"~
+)r.nt
a-rt':ifnc':-:; Y~[1:T br> introrlv('ed.:
:~net.ic~st
t-~
8~
'1']pr)i~Y
nSB
Dr. Palmer,
U~iversity Mcdical S~h001, SUCS0steri
Ilhyto:lcrnnczllltinin t8 repliC'n+,t" t,[-t.-;
T~~i~nn
,·~+-",';t
Only two patients Here 0,111 turE'd
~~is
Mannc~
t.he results
~n~
~ere
Photns
~he
~irroscor~
Leitz
8
"~3mera.
very paQ"'.
we~e
tRken
th-ro~gh
of a Leitz light microsC'on D us5ng a
10~s
Ea3"'j firatio!1 i-Jas lOOOx using t.he on ir:rler-
bI ',19 fU tAr.
'1';119
si-)lltter
speed was one hRl f sEcon4 Rna
the ], ight 'Vms ":}xerLU'1.
Tho nhotographs were then used to ore-
C0:rltrast
par(~
karyot.Y-:r "',
'In
3.!'ranr:e~ent
of C'hrornos':rr.o nair,:, in tho
r'ietaphase sta;:;.-; i: 8 standard array to stuc1y thp ('()mparative size,
sha~e,
and
~orpholo~y
of
~hromo~ome8.
EXPERIMENTAL DATA
TARLE 1
C'{ROHOSOHE NUMBERS O;-;SERVED
PATIENT
1..efls than
fIt
l\.
lV'h
.,
L~4
11t ..~'
()~.3)
1.1-8 or
more
it7
tetraploid
total ~e11 s
count-en
nercent
3.bnoya~f} 1
n
12.[,
7
hO
2
.-/'
(n
'--
20
1
21
1
2::;
16
J.O
21
1
~(
I!' 1
:-+
~-'
?
L~3
2
2
(I,t
20$3
2
6
40
2
SO
20
1
8
J8
')
..J
SO
2L~
1
~
r.::n.
I ,'1
50
16
J8
...(c'
.)
1
Bhm
AGL
),6
7
ACL
(; sw
CELL COUNTS
2(113)
II.GL
n
1
T'r
2 ( L:..E3 , RJ)
1
ALL
~~
ra
I>.
ALL
P
hz
CLL
(j
mat
r,GL
H
m:r
B
l! 1
I
rh
6
h?
5
17
.J mm
7
my~lorrollferative
(1
syndrome, metastAtic
1
1
carcino~a
- undifferentiated
)
"7
DISCUSSION
'l'he difference bebreen Acute leukerrJi.8 9nd.:,hroni c
Jeuke~i~
is in the
18uke~ia
Rcutp
d8~ree
of
~aturation
of the oe118.
the new cells are rlispersed from their zone
of ori s::n i r:'o thF c i reu] at-ory sys ter'! so rap i dl Y
there
",::,ba t
is not en(:>llgh tirTlt' for cnVV]nl.e-se cell rievelnpr:ent.
0:
In
'Phe onset
Acute leul\:ernia is rani d; the course; is short and severe
t i ssue'nrjltrati'2n,
infections.
buc(~a]
nlc8r-ations and r8spiY'atnry
\H thcut treatrlcnt death resu1 ts in three
months.
In chroni (' 1 f'ukellli:l the trans} t5,on from a nnT'!'1a:
1 ine to a ma.l ignsnt stern 1 ine 1 s much slo"rer.
progres:~es
pairles~)
stem
'J'he disease
Sympt'Jms inc1 ude a
slowly, and remains rrlild.
splenome[,aly or lymphatic glgndular enlarGement.
The pat': ent can usually survi ve three to fi ve yeArs 1r6 th
this condition.
Chr'omosomal variation in leukemia really became of
lntF'res-:; to Geneticists w1,en :it 'flas observ8c1 that qcnte
rn(~re
lpuke!"'5n is three to fifteen times
~ndivid­
frequent 5n
ualE wi:h the chr~mosome aherration causing Down's Syndrome. 8
Lat"'r
j-:
I-las found that. pf-ltle~ts ir:
3
·pre-leuverrlie"
condition,
,,,,ho had in thei 1'" bone mar'r()w a cl o~e of cells wi th chrornosome
a~normal
i
tj
es were very f:1uch I':or'" } i
kr:~l
y to dpv e
]
nr:
L'owever,
'fif the disease ooes not man5.fest itself . . lithi~ a n,onth
remains the sare as in
8soma}
comnara~'e
r8~jents
W}t~out
chro~-
el;anges. ,,9
The nresent -investigatio::l nllo1-Jcd for the ObSPY'VRtio;]
}~Tr~"aT:i.-.
l.C>1Jkemin, ('hro:Jic lyrnpl;at1c leuke r '!2R,
G~a~u'oGytj~
The
m~st
n~r'
chronif'
leukemiR.
consistent chromosome variations H"'re d'served
Ps'::;ients r~!itf'l a~11te l'=011ker~-la ('an be separater: ~nto
th'''ee groups: 9atients ';J1th apparentl~r nnY'm£'..l chror"csomes, patier:ts Hith D snAcif'5c C'hrn"'('s!'me at)1';0r~ality,
and patients
~n
whi~h
thp"p arp a
w~dp
variety nf
~h-C'oy:;oSOC'1P [1tJnorf"alities '~Jhir>h d:-, nc't. aCC>fl.rent"-'
c~~f0r~ t.n 8 ~h"~~:-,s~m8' ~attorn.
~u"h cha~ges
ir~ll1r18 yu e:~~"q'
8Y) ll:,l0iriy fmd j:)("YDloid~T, :Oltrllct"rp; re-arraHf:':ernents
arcl the -f"-ind~nn',
nf ahnorp'p'
-~
°
'-'(I
~8rke-r n}-irr1!"Yl,.If!,:rrlP8 :f l~nKnnwr t)r~p:1y").
D
_
'rhrpe " f
'18V-i
ns
eulrp"1'11
8..
88
1
t",p
":1r-!P~V'"
0
:-.-ot1e'lts
a"'''t.('' '3Y>aru' n('yti
C
st'lo~ed
dia,~Y)[-sed
1,J8rf'
1 puke)':li a :lr ch"onic ~-n:Tc'l '--'i 0
~egro male; II years of age; aOffl-it.ted
D at:; en t
!~ - wh:
-----l----,('C'El1]SP of aD::'!'ia and
8 "nrpleukAmic condi.tior".
:1p
Has diagnosed 8S 11a,ri.ng :V'lltP
granulocyt~
(' 1 eUKPmia
lrI1
thin
tHO HARks.
anc nredni S"Y;F'.
No apnArent
remission was noticed.
The,
~)atient
The "1"11
1 i t (' 8 'ed t
n
th e
:; 1 J ~--T 'j c i ()" :" f' the
~n' p
dis C 0 8 1 t. inn
r,
C~ 8 r, ~
,0
"" .
t.he Re'r>(",--."t-r!(' (OhrC';'10s0:1AS 'rrith satAllite" 0,nnt:;iY1
8 n en! n 1
" ,--"1 -: 1 p () 1 8 l' ') r g a f'. i z e r " seem e nt, t 1'" 8 "H~ 1 (, ('. !] ° n,~s
i>,"''j~ vl:l,---; -'-'1888 ~hrnf'1os()rnpS ~1By 1 ',8d tn 0-, "rn,2 r" s s i vel r S ," () f S'1 (' h "e ,. . j (J:1 8 •
:~' a r l v (' v t (', CI--, e rr~
1
As
t
t
1--, p,
,0
:1~d cyto1.)F~i :,a 1
n
stl.lnies ~;f (",qr~0·pr ~e~_l s' drp~J at7,~~ti:lr~
t, the D()ssi'>J1e rc'''.'''' of the nuc1eo:us in tl;JP
('1 a Ji en fl n +:-: e'1. '1
h ph a v -i n T' (K ('\ "[ 1 p r - 1 9 iJ ~ \. 1 1
~~it18ti()n
I) P
D
a tie n t
he c au s p
on
~h8
3 -
0f
hrn:
s w e 1 '1. i ''. [! and e ru ~! til) Cl 0 f
lower
extr~~i+ies;
'--)y
1 E''C S
n
1u S
H
S k -;
~
r a ;>h
cnmrlained nf back nain.
fi.rri 1 of 1Q71 tlte onc
<~i.n
nortio'!
c-,P
_'l
f'8r.~ 'trq~, rJropT;erJ rer.ause
blr::c'o ~n!'
:~",.,~t
~r89
_
~lih 1 te
nf neurnrrlusc1Jlar tnxicit:!.
')1,00 witi' 72% gY'anulolOytes.
':ohe
Prior t·; this
time, January 'q7~,
patient ~ received external rad~ation
+-,hera?y f:ir a chl,-rornRt:J1Js
rYJ8SS
at the nape nf tne r,p,ck.
Thi s treatment, induced J Emkooenia and ane1"11a of
8
mil d
degree.
Several oeripheral blood samoles were taken fr()~
patient R for nhrrmosomal
of' his di.seJrde Y ' ,
analysis durine the Dro~ression
rut it was n()t until
July, 1973, that a
sa'TlClle Has ob<:,ained whic"', '>P0'r1dpc1 :lc'leqlla+-,p 9".rowth.
t his t i
Y!'!
e t hp
n 8
tie n t
0ytoxan, prednisone,
1.>J
asp e c e i vi. n g d a sag A S
0
f
4t
\~ Yi/' 2 ~m
,
and dalmane.
Chromosomal analysis revealed an 80 percent normal
modal CC'1mt "'lith 2'] Dercent aneuploidy.
most of the
not
ma~ker
~onsistently
It a':JpeaY'ed that
chromosomes were in the C
gr:i~n
although
the same chromosome.
A:)';roxjrF"+-.el~T r:;n 'lercent of 8.11
granulo~ytir lAuke~ia who have
Datients with acute
been studi0d have
had aneuDl'!ld sterr! J';r.es in marrOhT nreparations.
Th sP 8he~nqnt ~l~nes nay be hyoodiploid, hyperdi 1 o~ d, or :,seud:idiDJ oid.
80ecific ster'l 1 inp~~ qr(~
~ener811y ~uite c~nsister.t in leukemic cellq p~,~
or.c' ~ ndi vidu8 '. .
!~l though sned f j c karyotYD1 c a~­
t""ation m8.Y dis80DGnY' during Y'e~ission, tr!8
" ..... .;ginal ,s~,:;m line :'lay rpapnear dur:n8 sl1ccessivp
re' aDses. r
0
;')and'H:'.r[" and his c)-workers als" sw)':)ort thjs viewDoint.
Sandber~
and ~o-wnrk~rs (lqA~) analysed
t~p "~romo­
SO''''J' cnrst:tu~i.~'r; ~n 21q cases of 8.cute leuken~a, and
fmnd a vp""y '!ariable DatteY''''' >~,?arly 5'i oercent o£'
t1t<? cases J..-nd 8D3upl.'Jid :"1orl'":: c::hrol"1oso'''':p n',Pl1bers
ranldng fro1"1 hy':JodiDl "idy to hypeptetra~)loidy, while
the othe!,Q ap!arently had diploid modes.
These invesU gato~s a 1 Sn f01md that ir. CDses of acute 1 e11k8r1ia~, wi th the same modal chrorr"scJlY2P mlr~:ber,
tho kary0·70e8 were different.
ComparativC' k8ryoty;:d.(~ anal~T­
'pc' of rr.ary ~Rses seem to jndicate tha+acute
Ip.ukern.18 ('ertr:in aut::S(in:es of S!'nllp r, are T.Q0re f'rc~Juently affected +--!"an othep ~h!'()mOS"l'les.l-
!",
Patient C' -
sw:
a spec:.fic chro:r1nsC':nal
the Philadelphia
at-normali.ty.
In most casps this is
chpn~~some.
Nowell and qunseY'ford (1960) demcmstr>ated R ~~,)e(·j fj c
('hr~f1;Js()me r)bD":;'~.8' ~ t.y :r' C'r.Y>'lD: ~ my?' (,:lcl 1 p'lke":ia,
_
8li.,i this
1
C -
rapidly ccmfiY'i'lBo.
'T'he ahn0rma itv f')UCl':l
(,Pl1 s j0 P-'e creat ;'1njr)r t~T;f Ci'iHJ
patients is a small C'hromosomp replacinr; one ,J' the
G-7rou~ ~hro~osoMe3 and Y'esu]t~,ng froM a nresui'lntive
dpreti~n c~ 8hout one-half to two-thirds of the long
ar'l: (hAt xx 0" XY, Ga-).
Thi s ch:romos:)r4 is a l ~n kn()Hn
as the t)t--JiladplDr:-:'~l or Ph' chromosome. 1
1-I8S
in blo(~d and 11larrnH
shOvlY; by the ('8se 'I+'
me~her
d 1 S t: 0 r
Ph'
hJins
~n
whicr o;:ly one
1
c::
the n8j~ had t~e Ph' chrr~0snme.·~
lf
t,~
rr',onn7,ysnti(~
Fifty nercent
d•
~hrl-=rr'10S0rr8.
nt.her
:1
n+'
her blood rells exhibiteo the
;::-'-110::83
o\Tera~1
+:h8
.prcqlJP~--';'~.T"lS
aho'lt PI, "0ercpnt.~r,
T~3t
nSO~0'
fU'rt,j.-,er chanF?:8s
hln~tj('
30ne8'r in
~r~8i2
~8y
he
s~bstanti8teu.
tBr:rn~"""'ll
'T'r,:>
p'r8~ed~rl
~y
~~
pd.:ter.:1
01.1'}~ge8.
idf~n~.i
t~
jlJst the Ph' (,hrom-
('JtheY> than
A8 1
£'o'rY~
g
8t<",ze'Jf ('HI, is usu811y flsC'oci"ted nr
n blRst~0 phase in whi~h the chrom0~;me
1 p'ike m 1J'. ,'p11 S Hi"!:;" Ph I u~o'2rcr; fu~t'JAr
rrhp .... ~::aom(;~()mR! (?r;!]n?es a~p not ne0c2·8aJ"liJ.~I
~y; 0' +'fererl: Dati ent;:; "ut h8'.T£' a tl;:'l;C'lCY v
u;:j f'orn, ::>a;-tpr:1.
The arp8arancc of t,,,,, or
chrn:rlUso:r108 \18 1 )8 1 ]"IT C'i'in~ide8 wi th the "Dse"'::
P'')'
nf t,he ~ln2t;(' nh.ase (Deder;en, 1968).
HvneYO"l[IJ,jj"
~ s thp p .. --.,;t ;~~J:"1:'~ (~.~ :~/PA rjP nn.ellnl ') ~.n~. T:!}!l ;'~h q> .... ~'.r,'!r:? .~
rlr:"'P
r
in P'l,'l'Y'r:TtJ ,.,ell s
ouri~;-: b1 ast~c '~:"i",; ;.17
.
rpsear('h.
Tho Rr:ntf' 1;l ~st ;-rnnsf',rmation ~n natient2 ,-!; th ('Iv;L
is 1Jsua1.1y a~C'":)r"lT'8r_ied by ~on8~dpr8ble i nc !'f'88P i.D
v81'y::>tyn i c l":,tahi1i+,y.
TY1.-n i 'lC the ::'hY>Ol,-i:- ~,h)s"
S0~'inl
[l
8":,"rl;P~
hl()od ()r b:>rr: "larY>()W lH)lHlll"
I,P
~hnw
f'n4rly C'''nctaJlt Jr!'l'ryn!:,;TDF' A1thnU8h 8neu?,1n;~ Alor:.'?s
b'?e~
r};1,,:.re
Ph"
Y"l:?"~';()rtC'o
f"iIroYl1o~');",e.
I)~r~nr~lir~~
(")~~!,>t
r::f
wi t'l 1. ('Iss
0+~
t"he
'i!'
wh.~("t.1--,
().p+/e~~
~n!1~G.j~
'Y"r'orp
+11 8"'""
:):r'.e
'T'rc'ltr-;ent fr>p'lUP:1tl y 'redur8S ":hp
r~t
a~~1.1t0
..
~··-- r<-!+-1"P~~
~}~~S0
'J~
"ells.
"!-he
rf.--"w~~·vpr
"'i.~~~S8,
'..J:i:'~
~h.O
an<);:T)1.8-}d~T
[;::d;-' :," ""hY>'JYf"'S~;'~n. 'Flre1 ated t,', the Ph
I
?o08T'SCr has
"'pem1"""':.
h(,20ll'l8S
S11GC es :: po
thA+- t.1-1,::>
ro.
t r tho
,,-0 +-h~ 4~ seas
f'1"r:m thp, chrnr;~
is oCTo.nripr;t tr: 8 1.'3T'se drz,;-8P (llj the
opveloo!"ent :,-0 are'.l.plr,id e1-;ncs.
',re !lIse: '~')'1pidpT'c>rl
nT'(,)?:T'esp~ ny;
p
8(,';+;8 stace
1-
+-\.-l~
('x()pr.?
~i3ht
01
i~~rpnsp
cells.
ano
8e l ;s to hp splpf't-po at
f nt.heT' nell ty!,ps and that che::'otherR?Y
1y':)ercn:,1r-,io ?h'-
the se1petiOlj of these
~ore
res~start
~
~eg8.karyoeyt.i',
dis,::>RSP
')')8~t~ve
rp~grdleqs
!J p 1"sists thY>(:mgh,)ut the ('0l1Y>8P 0f thp
of'
t~p
=p~e"R'
to thernrY.
resnn~se
::nwever, the ,,+-,he'" ,:--hr n ]'Y]oS"]18L ('1\8nses (-:0!'sec:uent tn
blasti(~
rlt;servntj on
1
s +:h8 re 1 qtion h o tl.,rrpy)
-f •
the ''''9.ny and wneth'?r t ':1e p A l~l ent-
1
~
Ar
}, !~!
t pre s t
~
,,~
().
'C)
Pr , nos ~ t-i 're
or YH:'gAtive.
Patients wit~ Ph' nositive CML respnr:o to therg~y
readily and survive for 8 ~uch lonce~ ~A~ind of
t-i~p than Ph' negative pAt~8nts with the sa~r ~!~e
of leukemia.
It is possible thAt Ph' negativ r CML
mAy he a diffprp~t entity than Ph' Dosi~ive CKL and
[Y'(1re aki.n to acute 1 ev~eC'1i8, partic.'Jlarly myel ',h' asti~
~rre
leukemia than tn CTJIL." ,
A secnnd
tyn,~
Patient D - rr:
of Rc.ute 1 eukemi a is acute 1 ymphr)c~rt i
Male, Caucasian, six years of age.
C~
He
At that time he was placed on the
b~r
ther'apy pror.:r8f'1 ontl ined
consists of three nhases.
Dnnn1d Pink1 e.
T.
RSf'1ission Induction Phase -
1.S
Hemissions are induced with Vincristj:}e
hody surface areR
(BSA).
mg !Jcr m2 of
One dosage weekly 1v.
predn;?::me is ad!'linistered IjO :ng/RSA dany -;n three to four
Jiv~derl
cn~nlet~
pat~ent
~s
dosages.
Th i s i s con tin u e cl f
remiss~o~
is entered
r; r
f m 11"
0-0 the ma~row o~eurs
~nto
ph8s P II.
at
If not
continued fnr nnother two weeks.
IT.
Che!ioth"'rapy is ';"it l 8ted after cC'mpIete
Tv
Tv
""- three da~Ts
f~llm"ed
b~l
ltJ0 P k
t~is
If
3•
ti~e,
c~~):np'lete,
Intens i
phase I
V"
re!'l~ss:,oy)
of the
mer.2aptopurine 1 grn/BSA/day
x threp days foIl O1>!e ri by eyel 0911 c' sp harr...i oe
hOO mg/t3SA
Iv x 1 day.
P~ase
the
th~ec
is a
continu8tic~
o~
U-:)0n (',onpletinr: t'Ie
"her'a!:,);;,.
therapy
!lr8
I;i
vJee]~
two
rest
siven is allovTed.
~eY-'~rJrl
inteLS~·,'(" ':)h3?'(, ~erL:'rl:f'
durinG Hhich no
The Gontinuat;:m
jYJec1i::a~icl-!S
~ons:is+;s
~f'
:,,:crcap-
+;~r~rine
SOmg/BSA/day orally; o~e weekly injecti~~
V~"('r;8-:;iDe J mc,!I~SA; mp~,;:ntrexa+,e ?() rr:C/~?PSA: arid C'~7C:'.-:::­
pho2nha:':ide 200 m[/rr?r<,SA/Heek Iv. 20
Patient D receiver' bv p lvp :-nnn+:'-1s ()"f' rf'mission en therapy.
r!O:
Patient E -
age.
cytopenia 8Pcondary to ALL and treat~~nt: rl) peripheral
and tr!?'Ctm nt.
of the
:-he
~vas
louk2~ic
placed
dured only
ccnditlon
011
~artial
8~d
an advanced degree nf relapse.
COAP troar;;r,p;-,t hut,
~'1Ultlple
p-0fc)1"ts
0:r",-
remissicn.
patient
l;any
(\ Tj,-'
,. ~ .) )
(F1gurE' 3).
fi
ft~'.
Doubl~
m1nute chromosome format1on or1g1nates
::::0,;
'lre
1';7?,
.T'~,:p
,--r,ns+- i
~:v'"'nf\1
~:~l'")-:.r'·npy>~1
)-'8'18 heen stlJ,dyi:!G the
~1"'~
,:"f cPJ 1 ~ ie' :he n()'l-" rrJa:r Yw - ' 0"'.0
HE'
",:~Jt ~ ';'1.
in
h-'_0r~(~
-
] )
,.
"li,yith aC1.1te
~rl~.l_r1ren
8.5 q[';nr-s-i ;c;, a'1d th1")llghollt +:he
:~: ""'("\y-:-J.-.l;/· r;e""T{)~ (")f-:;;'1
t-r·(,:~lY'j=-.q.l~t-?S
f~ ~atj(}:n
'~·f
J ~.:-:)-~P h C-: ~,~
~ .... +-
f~~...l~·
i
1 p'11l~ 0
~
3~ di~~r.--;~i2:
"Yl
I n.
t'J~")
e]. fJ ~ .J
to the
~,''''(>-rd~v-,cr
lE'~11·~etr~iq
tr:p di
')f'
;-:o':eo--~
c:r'
.{l
,....t-r. Jct1.1re
("l~r(_'l:~. .~:-\?,~)~r~pl
,~1f:l8;:;e~
('o~J.1"se
T'r:... n~
1. -r~~! -: ~ p
~
~d('n.J-~-
-:
~'')p~"!}C
arp
l.)~pd
iT!
a "': =_ ~ ~ ~. ~
0"Itl~o:ent-?t:C'
~ ~ t. n
[!,';._,?1:r~-i8
n~~ct(;:v'=.r~f1~tl;; h_~:Y'c~:i:n~_~,irl
"'l)
8-:
"'P8C1"'.
(.=-;1.~3ht
'_""'r-71 P S);'J) 1')nrmnl .,;011.8 tlj~8th~r ~/it;h an u0~q_si:jnal
~l yn e 1" rl-i D 1 :1 2<] 01" Y':3 p, 1.1 r:'l r rl -i. D 1 n d (' e: 1 ( t "11 :~ a s~ ~ ) : :,\ r;:~~;-,<"',~~~~,l~l~d f~Y"\e ca~~\; '~f1d :i) rl~r:181 ('"',r..':''Jf:).
T'1' "~!v"'0'" .:../"
·:n~~;·~c ,-~:. . t~pntment 1.r2 AliT),
tl--:c
(~Yl~n"t,rJ
r'
n~)+
d,--es
T:
"l
'"~;-·'··-·"("('\-Y1t-
?::':j·:-;.Y'1-!:-·4
r-
'.~l,;..;~rl,
l'Yjpr'\t:f-i
~?'")! ~-:r~
:?7T
ldl1(~t.h:"'\-,
t
re~ppp.fa~
ri!-""'C'0
'C-<
_ _
81- Y
I')rn.<-~:-a
~,0'1""1
~0
nt
':'01")J
~1,
nf"l
t"
!\~
('Y"I
_ ; "
.~V1,-"p·-'
1:
(-'
:': 0·.... '1r":!
V"
r: ~~.L
-,
(-,r.-
+~-
r
( ..
C"' ' r . ~ [J
;-'~':;,
(~i~
+-
l_~~~.~, :~.t-~.,: ~~ (':
f..
~") 0' ---~~; ~; p ,
n
-~
T ':!
, f)
~-:. •
~
1
:\~.:1\.C'~· . .~1 =~
..
(:llt::-.~~~·~. R
t n 1
1,-.Ji
t,1;
+-,
v
.
~"~· y~·'I ...7lar
t~:erp~·
......:7.
Tnle~,
VlAD.. '()r0··'~i~
T
~ e;; f.: ~
f: '''- . . . ., ,0 ;- ~ tl n C A
+-,1.-. (,
•
, ..~ '~r
~b.ar~('+,~~?:rS_?:~',..:J
::1 t ~: is=--. ;;T r:' 1. e .- ~l ~';
.p n ....
r:.;
~''1~:,T
~~8C1J.9::t~ '~,'"
~t:::1"Y-'dl.n h1 R. ~'~ ~ ..
"·"ll ~
~hn~
ry:0~:':1
0('(,lJr
,..}~"':r~'-~\(-!..-~ds t~·--~,
"13 ~-.tll~f-'"
r.i. ~
Y1
n~S0~~f1t""'-...:
1 -: ~ ("I;-'(·r--·-v"-('~("'rn_
....
' _n
"
" ') ') "
'. "
j
o-r
qn)
~ ~.1~
n
. . . '''1:)''
i.:"'
1
a.~1.1t~
,\-"'1
~ ... L~l q ~l ~.~
.!
r.h0,
i s
,.--,P
r~?Y~~nt
-"(,"lnd at diag:--:ns} s."
+h()s-~
r .. ~,l1~:-;
we
!1~f~;)r:~t
re1Rr~S:".;
T:'l1}11!
.:')+;
•
':
~,_ • ~
ril1_:'-'1~)nrs (f]h,,)'v"""
'111-.('
:"('1Yl':19. 1 it~; •••
·'~:;r::n","')~~~-ir--,y.
l':-n8v.,1 the
"jt)?l..
:-10P18+.. o~_n~~~(~nJ
~,::>10+-pa
·~~!tc'·~e!1et.;(..
:,0
~() f.;x~!'1-inp t!Jf? ~)~ti.e;t he:':-~Yln '~~;~1 ~ ~r:~~~­
i~.
tr(:
1,r:
-:Y1mp,dlq~.("'.J"
q~
,"\
-r
:"! *:
~1-)eYn
~~ S
.;
r) ',: :-.
r'l f'
ro, r-- .!
C"'
r_ ~ ~
Y"-J?-sapnas,,"s wi th qn anellDloi ri ~hroP1os()me ennsti tution
in an 0 th e rH i s p ~1() 1"r'lA 1 '11tl rY'01,-j r~,ay h P :'"'''1 1 rl t-'n,:-, T"", 9YJ 2 e
r"'+~ :tlr-1]t~ 1 elJ'{Rrr~i ~
qrc1 th·j
rna"'"," '''"'r:-L~TP
'r'l111R"t)~ (~
-5 to be
••
Pi ~r::lrf'~l tj,~
'the thii'o
of
inde v
;
r
_...
.'.
C'
_.,
{:
1..'
(~hpm() th·~r:J.9Y.
('lqssi+'~n8t.jo"
of
~
."",
<-
f")
.'
Inu)r"'~:-1-:'''l
studips
"o"s~2:-ed
nat~ 8f'tS
':T E'
bcnp
~Rr1"CW
nnqlY3is.
with
sheet~
o+'
chI oramhuc i 1
~E'lJS.
!'l.~d
,)rp rir. i sene.
wa s
=
PIGURE ;:;
FBI.
"tt.Y' p ad1J:"f
pat 1 rmt !\
8P~ondaY'Y
Datient ('
---
x
can8tY'i~tinns
was
.I'mother
as to the
of this
sisnjfi~annp
~8rke~
8hramosomc.
Gunz et "'_. (1 q6?) found an abn(;Y'nlal G fjrnup ,~l;r{)rrI080::P se~-Tr:\:::at ;",C 5.n [} fam~:.J y in Hhich tl,rn merY!:>"''''s
1".rV8:r~C
aff(-'(~trJ,~j
seperal
l·J:.t~1
·r:'t~nY·
cr1");;"1~()S('('-:~1
C'llrnni{~
lleP1bcr~"':t
b'-"~:-
....".rn~p
8l
SlI
l-:rrnphoc.ytic- Ip'lke!Y}~_f-\;
(\~Jrr~ ed tll.P:' &bn . .-,~")!~q!
()th:~~r1...rj::1e
l..lnaffecte--1.
~1r)t~=T
this r h r0mnsomA predisDosed to the
sU3cest~~
t~st
-"Y't {f'
dE".reloI)Y
eYY'oni~ l;'_Tmphocytir Je'Jkemia.
'T'l[i8,
'1C1:Tove:", :"9S nCVl;Y' her;;: 00nfj :"mAQ and j t see rr:8
l ·p-el:r ::r·a t the oono":':8. l ehrm'1'Jsome whi('h!~J?:3
tc'''neo t'0p C rist~hHl'·~~ Chr0T""''30rne, Ch', anr! ap"!:'eareo
telocen+ri c (G1)-), l<.JQS a :1ormal variqnt of t9-fl
karyoty-:-p Hitr !itt:A clini~81 siGnifieance.'-
blastj~
T~ere
crisis.
H88 A
DruG
~S2reDS~
mild anj soC'ytosi
P,
the~apy,
i~
the
[::Jik::'
COAP, induced remission.
n~lmh8r
')~yto;".is,
0f red blond
s~118
with
and rn};ycnromrsia.
!11-
L'lere was
an 5ncrERs8 ;r
~c~ted,
s~ze
number of white blo:)d cells.
or hpr! distinct breRks.
fai'in~
hut
nuel eol i
t~p
•
to
2(_p~r2~e.
These breaks wouJd
per~:t
- 1S
-
GONCLUSTON
divide the
ti~c
sis from the
(~o1Jrse,
thi
~
P
dtag~osis
i at i 'In
re:niss1 0 n,
t":erapy,
t>t"rq~
y"'lay
cons~
c;':~'h'.:1'3
st '1 arcp1y of l!1,':lY'ies t')
oreBk -in
<1
('hY'orr:n<:'(Y'~p
'J.
TnjlJries +-, ":-lro~0~o!1'1C:'3 hy
y I ,,,t>-~s'- :,rJ th" coIl.
f't
_.r
hre~;"'.""~
rpJ8'1se.
r.:1rJ
e t empnrary m'0 n p-:"Planent
~rodu('
~>!.~
erhs
C!+YlT-:'C1.
ionj7~r,c
Y'Stl2at:":15c '"1re
,., :1~ists
t~-:J"".I :_c)r:s :',f' ~C'A~tr~f"'o
rln~~rJ.~p
ThA
llP'J811
.~
throu~h
of the disorder,
f'hrnYnoson"'p St 11di8S were don".
r.nuPS aftAr t"":at'ler:.t;,
eh YV)n'!os:J"1es,
series of new research
8
.,: sht to]"E' :-cpvAral yr"8rs, hlJ+- at 1 east a
th9~:
blood 89.:"::018,
~~p j
0
c~nstruct
'"'nd:iat~('::
rh"Y';0th?rapy,
Of
and
~atpri~~
snn
e;"lrcr-~('·nor"1es
c'hro~osrr'-" f!~"~~~~YlJ:~t9 r~-:...:rine; sl.1b8equent :~.~ t:-)s~ ~ ,.
Tr:~;.
d~;"''--lid
--"-"'1 1
..... 1-,0 "~,'8S
n'f Chrr~~)(,,;~n:i1p -08T'"a+S ~p~l]l~~ :~r::.
.~C\ ~ F;
~:- f ~
rr:c:tq.> , l.":
r
c.
t i (' r~ "I
~1;Jl)~d
SO':,]A
n~
1.
~..
•
"1n:-;~~"
!t~Y'l.i7.i~f
,- r)
'-
8 (--
v
r+~,-:-.;c
0q'~'~rr~
"s.
('n:;;0P~@ater1
~r~
l!...,J ..
~n;,
y~
~.cl~, 1_.~l HJ"l
-:
:-
:-;
'nl
c, ~L ~_
<!.:ne
V~
3:'1,)1
nt
r~
!'i_s:r~8~0
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ACK~JO\rJLEDG EFEN'I'S
Sincere appreciatton 1s extended to:
o)
The i:)al I St atr~ Un i v!'Or'si ty TTr-:i8 r[';radll a to Re s e arc h
?ouniation Pnr
SY'nnt~ng
rr~~ect
the funds to make this
D088i bl,3.
h)
Dr.
~eor[';e
1:os;'~ t8~1,
f'lr
T~.
Sranar'1,
811~nlyin3
-;JaPlOJngj:-~+,
;)'It
of- '-)a 11
1:emor"ia 1
n;:t1y the patLmts to he
studied .• but a1s:; hisvaluab10
tjye
ir: 8nsHerins 'luPs-:10ns
research.
(')
Dr. Stepher. CClb'lrn rmd Elair:p Leykauf,
c:!tr:Ge:r.E~tics
toch:ri,~iRn
r!'OsT'ect~vely,
State :Jo.spi tal 9.no Tr,gjnin,r:; C8nter
culture
chromOS0~~with
11.'8(' the nse-f' P',e
8
C',tat,
f~ir
bioC'he~y;"st
nf th" Pnrt
teachinG
::J8
~,.rByne
to
re18t~vp
degree nf success.
-Tnsnitnl
fr'('lJi+-l(~S
Wf:~
r.nd
:"-:'!,C~l
n T NOT E S
P 0
Pra~tice.
1.
'T!3:rhoe, P.G.J. Leukemia, Rese8.reh and Clinical
D'Jston:
Little, ~'!"'oHn, and Cnmpany, 19b"n:" Tl. 10 •
.?
"9usch, Harri
Y0r~(:
i\~ader1i~
8.
The Fol ecnI ar n-:
Pr-8SS, 197L.
n.g9.
Ibid.,
11.
Ib5rl.,
no
-; ,
01or::v~f
Cancer.
--
.
~
KoJle!"', Pea C.
Recent Res~1ts in Cancer Research - The
!101t> of C:hro~'10sJr~>3s in Cance:r Biology.
Ne~v Yor>":c;nringer~a3, 1972. Tl.?O.
6.
IbSd., ;.
1. 0"
'7
P:r~est, Jean 'T.
(;ytor;cnetics.
Feh-lce!"', ] 969.
p. 70.
8. Wintrobc, ~axwel' V.
Lea ~ Fe~i:e:r, '9G7.
(]
Koller, Per- C.
Ope
Ph51adel;hia:
Glinjeal Herrratol 0 gy.
Lea
&
Phi' adel ~loia:
eit., n. 76.
T-fuman Cytogenetics vnl. 2. Ne 1.: York:
1 'I
Acader'i5 c P!"'pss,
aiL, Y'. R?
'1.
Koller, Peo C.
}3.
Koller, Peo C. fin ci.to, '0. 66.
Ht..
T~arne:rtoYl,
..
1 I
1{ r; -,
1 P
r,
OPe
Joh'1 L.
-:> '? ')
c.
or.
~j
t., p.
~J
S•
16.
Koller, Peo C.
19.
Bll S ~ h ,
~a
on. cit., p.
()~'.
r:r i ;:: .
Pir.:".-le, Donald.
21.
Sanjber~,
??
Lal'."]_~r,
Genf~ti_8:'
,:),..
'-
71~.
t- • ,
n• •
00/
to
Cancer.
A.A. et al.
S:T}.\!i.~1
vj1.
:-: j
66.
Cancer ?Cl:
:-1., T.I'lrna
:)eC~~8r'
,Tune l Cl 7J. D. lr:].
to:::,. " j
t. .,,-,
Q
q
'~"!aJl'~er,
,q~d
R~r,'r,-.
~~arrl~st~.r.
:=> i;,
•
L?l.
1~()2.1er,
~
ra.1.
',',-
,
Ko', 1 er,
PRO
("1
"'0
1J,qrri s
.
Peo
.
("1
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r),i
.
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riP
~i ~.
.
t"';
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"
,
0
ci t •
n
. 32.
. 101,-lOit.
,
n
,
,....,
1 oli.
LITFRATURF
York:
CIT F D
Busch, Harrls. ':L'he Molecular Blo1~ of Cancer.
.A,cademlc Press:-r9~
-HaDlerton, John 1.
Press, 1971.
~n
Cytogenill£! vol. 2.
Ne~T
Ne~T
York:
Academl(~
Hayhoe, F.G.J. Leukemla, Research and Cllnlca1
Boston: Little, Brown;-and Company, 19bO.
Practic~.
Koller, Peo C. Recent Results in Cancer Research - The
Role of Chromosomes in Cancer Biology:--~York: :sprlnger-Ver1ag
1972.
Lawler, Sylvia D., Lorna Seeker y,:a1ker, and R.M. Hardisty.
Genetics 74: Proceedlngs of the Thirteenth International
Congress of Genetlcs. June supplement, 1973 No.2, part 2.
Littlefield, L.G. "An abnormal cE"ll-line ln a patient with
acute granulocytic leukemia. Cytogenetlc studles before and after
an aliogeneic marro~1 transplant .. " cancer 29: May 1972.
PP. 1281-86.
Priest, Jean H.
Cytogenetics.
Philadelphia:
Lea & Feblger,
1969 ..
Sandterg, Avery A.; Masaharu Sakurai; and Robert N.
Holdswo,rth. "Chromosomes and Causation of Human cancer and
Leukemia, VIII. DMS Chromosomes in a Neuroblastoma. 'f cancer 29:
June 1972. PP. 1671-1679.
v;lntrobe, Maxwell M.
Lea & Febiger, 1967.
Clinical Hematology. Philadelphia: