chronic myelogenous leukemia Association of a ...

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1987 70: 1338-1342

Association of a chromosomal 3;21 translocation with the blast phase of chronic myelogenous leukemia CM Rubin, RA Larson, MA Bitter, JJ Carrino, MM Le Beau, MO Diaz and JD Rowley

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Association

of a Chromosomal Chronic

By Charles

M. Rubin,

3;21 Translocation With Myelogenous Leukemia

A. Larson,

Richard

An

identical

reciprocal

arms

of chromosomes

3q26

and

21 q22.

patients

with

leukemia or

and

variant

The

HE

CELLS

quence

of this

ABL

the sis

t(9;22)

is accumulating

bcr

genes,

are

the

that namely,

plays

of

the molecular fusion

a critical

role

conse-

At

diagnosis

and

during

the

chronic

phase

of CML,

the

blast

before

or

during

chromosomal a few

most

common these

recurring

found

ofacute

t(3;3)

[also

ANLL

80%

of

been

and

first

(ANLL)

identified.

noted.

are

These

some

reports

as

netics

Laboratory.

logical

features

an

the and

ins(3;3)]

megakaryocytopoiesis’’9;

sity

the

Departments

of Medicine

and

in cases

Pathology.

The

18,

Supported

in part

FGO2-86ER60408,

by

1987:

accepted

US

Department

by US Public

09273,

CA-16910,

Cancer

Research

Foundation.

Career

Development

Oncology Society.

and

M.M.L.B.

20,

of Energy

andby

the University

R.A.L.

Grants

techniques blood

accelerated

phase;

from

the

Fellow

ofthe

CA-

of a Clinical

American

Leukemia

Presented

in part

Address of

at the

of Hematology. reprint

The charge

payment.

“advertisement” indicate ©

/987

this

to Charles

M. Rubin. of

Society

article

This

article

must

accordance

with

were

therefore /8

U.S.C.

the Joint

Medical

defrayed

ofthis

be

in part hereby §1734

& Stratton,

Inc.

studies

aimed

chronic

based

on

were

biopsy

to

I was

in phytohemagglutinin

hours

medium

and

analyzed.

The

described23;

and

(24-hour) cultured leukocyte-

first

proposed

International

used

the

chronic cells

criteria

were

Chromosomal

according to the ISCN Southern blot analysis

the

short-term

at the First

or

during

(PHA)-stimulated

in Leukemia2’

clones.

aspirates

studied

during

from

fluores-

marrow

methotrexate-synchronized

were

aspirates

fluorescence

were

studied

and Potter#{176} and accepted

on Chromosomes

and

reverse

on bone

cells

characterof peripheral

quinacrine

patients

also

Metaphase

of the Philadel-

specimens

green

performed

morphodiagnosis

therapy.

trypsin-Giemsa,

All three

and The

examination

phase

using

samples.

patient

clinical phase.

Morphological

marrow

cultures

48

with

of acute

for

by

Work-

for identification

abnormalities

were

of

described

(1985)22

of DNA we used

from patient

DNA

probes

I was performed specific

for the

as

human

receptor (TFRC) and Hu-ets-2 (ETS2) genes. The probe contains -1.6 kilobases (kb) of the 3’ untranslated region ofa human TFRCcDNA clone24; the pTR1/7 probe contains 2.5 kb from the TFRC cDNA, including the entire coding region; and the pH33 probe contains I .0 kb of human genomic sequences from the ETS2 locus.”

of

American Section

RESULTS

Center, by page marked solely

to

Clinical hematologic

and hematologic features. features of the three patients

a t(3;21)

men.

0006-4971/87/7005-0007$3.00/0

1338

MD,

Chicago

IL 60637.

fact.

by Grune

of

in

patients.

pTR48

1986.

Ave. Chicago,

costs in

Meeting December

University

S Maryland

publication

Annual

Francisco,

requests

Hematology/Oncology,

Box 420, 584/

28th

San

the

transferrin

Cancer

America. Society

three

from

chronic

tissue.

was

of bone

phases.

previously

of Chicago

is the recipient

Award

in

in all cases by identification

unstimulated

Rowley

DE-

No.

CML

chromomycin-A3-methyl

peripheral

abnormal Contract

Service

has

METHODS

in the

institution

banding blast

Univer-

AND

presented

analyses

and

of

1987.

Health

GM-07190,

is a Special

June

phase

ANLL. abnormality

of CML

patient

phase

and

before

cence,

shop March

blast

smears

obtained

of

of Chicago. Submitted

acute

for molecular

in hematopoietic

of the

conditioned From

of

of CML

was confirmed

Cytogenetic

non-

inv(3)

phase

conversion

Each typical

chromosome

blood

one

include

and

of CML.

the

a focus

the

phase. abnormal-

The patients we studied had been referred to the University of Chicago or Michael Reese Hospitals; specimens of bone marrow and/or blood were analyzed in the Hematology/Oncology Cytoge-

evolution.9”

in acute

chronic

phase.

ization

The

at least

with

identified

blast

will provide

understanding

phia

however,

i(l 7q);

leukemia’2”3

in

abnormal

have

finding

the

of the

Inc.

abnormalities,

with

of CML

secondary

observed;

individuals

promyelocytic

interpreted

with

Numerous

been

+ 8, + Ph’,

abnormalities

leukemia

t(15;17)

phase.9

have

are

in

specific

lymphocytic

abnormality;

abnormalities

of these

is

Rarely,

the

cytogenetic

abnormalities

only

of

sole

these

time

observed

cytogenetic

phase

MATERIALS

uals

the

blast

the

not

in the

t(3;21)

of

tional abnormalities are Subsequently, karyotypic

usually

the

CML

Serial

the

near

have

recurring

& Stratton,

pathogene-

addifound in 9% to 30% of cases.#{176} evolution occurs in 80% of individ-

is

with

blast

of CML.35

t(9;22)

with

We

with

a new

clone.

that

evolution

phase.

patients

by Grune

association

at

of

primary

characteristic features of the corresponding We identified a new recurring cytogenetic This

the

of sequences in the

1987

clonal

blast

) is

t(3;21

in the

demonstrated of

of the

the

CML

Phase

M. Le Beau,

a t(9;22)

patient

a result

) in >500

with

at the time course

as

Thus, S

Michelle

than

one

ity associated

character-

is present

other of

t(3;21

only

a product of a I), or of a van-

throughout

rearrangement,

and

all patients

(CML)

chromosome, t(9;22)(q34;ql

and

three

the

J. Carrino,

development

Philadelphia was

abnormality occurred

a standard

a

John

Blast

D. Rowley

studies

male

in all

)

of virtually

The

CML

in t(3;21

leukemia

translocation.”2

of diagnosis of disease. Evidence

in three

clonal

the

long

myelogenous

by either

cases.

myelogenous

of this

was resulting

In two

ized by the Ph’ or Philadelphia reciprocal 9;22 translocation, ant

found

A. Bitter, and Janet

in bands

chronic

accompanied

LEUKEMIA

chronic

was

abnormality

).

the

breakpoints

of

translocation

(Ph1

between

with

phase

always

9;22

21

)(q26;q22).

blast

was

chromosome

T

t(3;21 the

(CML).

patients

translocation 3 and

Mitchell

0. Diaz,

Manuel

the

are

Each

hydroxyurea patients

summarized

had

and/or had

long

busulfan

splenomegaly,

Blood,

1 . All

in Table

a relatively

Vol 70, No

chronic was

and

The clinical who had CML of the patients phase during

administered.

patient

5 (November),

2 had

1987:

and and were which

All

three

lymphadenop-

pp

1338-1342


T(3;21)

IN BLAST

PHASE

Table 1 .

OF CML

Summary

1339

of Clinical

Courses

and

Hematologic

Course/Feature

Patient

of Three

Patients

Chronic

phase:

Duration

treatment

Accelerated

t(321

)(q26;q22)

and

CML

Patient 3

66/M

30/M

Hydroxyurea

Busulfan

36

60

-

Fever,

-

Fluoxymesterone

14

-

2 8.7

Hydroxyurea,

Busulfan

31

(mo)

With

2

Patient

41/M

Age/sex

phase

Manifestations

Weight

Treatment

Splenectomy

Duration Blast

Features

1

(mo)

loss, splenomegaly

pancytopenia

phase

Hemoglobin

12.5

9.0

405

50

13

WBC(x109/L)

86

23

2.3

Blasts(%)

41

61

34

Platelets

(g/dI) (x 109/L)

Bone marrow Blasts(%)

18

90

80

Morphology

Nonlymphoid

Nonlymphoid

Nonlymphoid

TdT

Negative

Negative

Negative

Number

Increased

Decreased

Decreased

Morphology

Abnormal

Normal

Megakaryocytes

Treatment

and response

VP

NR

-

VPD

Normal’

NR.

-

VP

DAT-’NR

Survival Overall

(mo)

survival

Abbreviations:

(mo)

V. vincristine;

P. prednis

1

1

2

46

37

64

one; D, doxorubicin;

A, cytosine

arabinoside

NR.

-‘

DA,HDAC-’NR

; T, 6-thioguanine;

HDAC,

hig h-dose

cytosine

arabinoside;

NR,

no

response. ‘Bone

marrow

megakaryocyte

aspirates

athy. Patients during which weight,

remission

3 had

patient

3. 1 6 kg

fluoxymesterone. patient died

at

within

not be obtained

because

not be assessed

an

identifiable

accelerated

1 underwent

removal)

and

of

blast

Blast

cells (patients

nonlymphoid

(spleen

3 was

Following onset of the blast 2 months despite vigorous the bone

2 and

marrow

3)

at

morphology

transferase

relatively

from

the

and

were

(TdT)-negative

high

platelet

Patient No.

1

2.

determined

his

bone

peripheral

and

each at

ses

Cytogenetic

phase

had

a

blood

1 had

x 109/L

during

the blast Studies

a

19

months

patient

subsequently

loss and

With

t(321

a

an

10

13

46,XY,t(9;22)(q34;ql

Blast

PB, 24 h

13

46,XY,t(9;22)(q34;q

22

19

blood;

BM,

bone

marrow medium

aspirate;

24

bone

marrow 1).

phase

The

character-

which

was

1)(100%) 1 )(q26;q22),

1)(54%) 1),+8,+

1 1.i(8q),t(3;21) 1), + 8, + 1 1,

+ der(22)t(9;22)(q34;ql

h, cells

and synchronized

cultured

with

for

methotrexate.

24

hours;

1)(5%)

1)(16%)/48,XY,

1)(q26;q22),t(9;22)(q34;ql 1)(68%)/48,XY,

1), +der(22)t(9;22)

+ 1 5,del(7)(q32q36),t(3;2

(q26;q22),t(9;22)(q34;ql

leukocvte-conditioned

I.

and CML

46,XY,t(3;21)(q26;q22),t(9;22)(q34;ql + 15,t(3;2

PB, peripheral

19

splenomegaly,

1 1 )(46%)/46,XY,t(3;2

48,Y,t(X;9;22)(p22;q34;ql

(q34;ql

Abbreviations:

Fig

course of his the chronic

1)(100%)

i(8q),t(3;21)(q26;q22),

ohvtohemaaalutinin-stimulated

analy-

Karyotype

BM, 48 h MTX

PB, 24 h

was

in

t(9;22)(q34;ql

accelerated

increasing

large

count

illustrated

All

typical

)(q26;q22)

46.XY,t(9;22)(q34;ql

BM,48hMTX

Blast

and

contained

of cytogenetic are

diagnosis.

only entered

by weight

of Thre e Patients

9

PB, 24 h

2 and

following had

No. of Metaphase Cells Examined

24 h

results

in Table

examined

ized

The

blood

(q26;q22)(95%)/49,Y,t(X;9;22)(p22;q34;ql 3

samples,

The platelet two patients.

1 was studied at three times during the The first study was performed during

phase, cells

analyses.

summarized

Patient disease.

Patient

etic

are

Accelerated

Blast

marrow

phase, attempts

deoxynucleoti-

of Cytogen

and

t(9;22)(q34;ql 2

from

with

Source

BM,

were

treated

case.

Results

features

numbers of micromegakaryocytes. not elevated in either of the other

1) or peripheral blast

terminal

of405

Phase of Disease

Chronic

of

in each

count Table

(patient time

cell

phase,

phase,

splenectomy patient

fibrosis;

fully.

induction.

blood dyl

I and

could could

morphology

1)

1), +der(22)t(9;22)(q34;ql 48

h MTX,

cells

cultured

1)(1 6%) for

48

hours

in


RUBIN

1340

ET AL

A

Iii

U

a’.

Fig 1 . Partial karyotypes of three metaphase cells demonstrating the t(321) and the t(922) or t(X;922). The rearranged chromosomes are located on the right of each pair of homologs and are identified with arrows. (A) Patient 1 : G-bands by trypsin using Giemsa. (B) Patient 2: R-bands by fluorescence using chromomycin-A3-methyl green. (C) Patient

refractory

to systemic

marrow time

oral

metaphase of blast

were

cells

phase,

present;

chemotherapy. studied

however,

6 of

Still,

had

two

only

related

13 metaphase

all

At

from

blood contained a t(9;22) as the only remaining 7 contained a t(3;21)(q26;q22)

the

predominant

clone,

studied, had 48 t(X;9;22)(p22;q34;ql t(9;22),

was

8 and

chromosome

remaining

cell

abnormalities

clones

comprising

In

and the to the

2 and 3 was studied phase. In patient

in our 2, the

addition,

49

a

metaphase

these

as

the

Ph’.

3; one was

We patients

cells

long

arm

ofone

DNA

analysis.

locations

ofthe

karyotypic

extra

arm

contained

of The

these

related

pseudodiploid

21q22

correspond

gene26 and transforming

The

To determine

loci were

rearranged

we performed

mapped

the

two

blot

analysis

phase,

netic

analysis.

The

cells,

with WBC

41%

count

were

Only germline the probes. Thus,

the

and

TFRC

or ETS2

of the

translocation,

of DNA

of patient I; placental DNA which had been digested

concurrently

of these

megakaryocytes. detected with

of

the

3q26

TFRC

sequentially sample had the

sample at

blasts

that

and

patient,

whom

in three CML

we studied

male dun-

serially,

we

We

have

not

observed

a t(3;21)

in

from

used time

gene

36%

nancy (M. observations). the

these

of

Mitelman’s

Catalogue

of

failed to reveal any One patient has been in the blast phase of

on chromosome we have identified

associated

with

the

3 differs a new

blast

phase

of

microwere was no

two

synmalig-

the

may

rather

to previously

of the

identified breakpoint

in the which

are

D.

3q26

abnormality

found

in

of exposure

to

evolutionary

CML and the chronic

a t(3;2l) had phase; two of

busulfan. are of interest

with

abnormalities corresponds

t(3;3)(q21;q26) associated

unpublished to be therapy

a spontaneous

cytogenetic in

Rowley, is likely

be a result

agent t(3;21)

patients

same

also

than

the alkylating

breakpoints

of

in our

three patients with chemotherapy during

received

The

two other

patients,

CML

agents

breakpoints

studied

developed a myelodysplastic chemotherapy for a prior

Le Beau and J. Because the t(3;21)

with

All

from

of whom cytotoxic

in these

The

both x

M.

mutagenic

for cytogewere

and

the breakpoint cases. Thus,

marrow

patients

mia.

restriction fragments in this patient, there

in bone

laboratory, both drome following

event. received

periph-

86.4

literature

abnormality

mality

to two TFRC obtained at was

the

CML.

induced

was used as a with EcoRI, been

of

Chromosome Aberrations in Cancer” other cases with a t(3;2l)(q26;q22). reported as having a t(3;2I)(q12;q22)

M. A

The t(3;2l) is not entirely specific for CML, however; the same rearrangement has been observed as the only abnor-

other

one contain-

bands

positions

the

evolution.

recurring a

2 of the ets sequence of the virus E26 (ETS2),27

whether

or PvuII, was hybridized an ETS2 probe. The

blast

at

as a consequence

Southern

eral blood cells control. DNA, and

the

t(3;2l)

of the human homolog avian erythroblastosis

respectively.

Hindlll, probes

to

ofthe

In one

CML29; however, from that in our

sub-

and

chromosome No. 7 [del(7)(q32q36)]. At the cytogenetic level of resolution, breakpoints

phase.

t(3;2l)(q26;q22) chromosome-positive

review

had

with

or

showed that the translocation has occurred in association with the development of the blast phase as the result of clonal

ing an extra chromosome 1 5 and a second Ph’, and the other containing these abnormalities plus a deletion of a part of the

l09/L;

identified an identical with Philadelphia

cells

Three

evolution,

TFRC

>500 other patients with CML in the chronic phase (M. Le Beau and i. D. Rowley, unpublished observations).

abnormalities.

further

the

translocation, of the standard

The simplest of these subclones had a standard t(9;22) and

only

undergone

and

second

other two were hyperdiploid. had 46 chromosomes and had

22

chromosomes as

in patient

t(3;2l)(q26;q22)

of

,

well

found

subclones

21

A three-way is a variant

within

DISCUSSION

abnormality, in addition

an isochromosome of the long 8 homolog, and a t(3;2l)(q26;q22). I I

had as

were

patients of blast

chromosomes. 1), which

present.

chromosomes

one

from time

breakpoint

quinacrine.

lines

ing blast blood at the

using

genes.

peripheral

t(9;22).

Peripheral laboratory

by fluorescence

for a translocation

ETS2

the

pseudodiploid

cells

evidence

I 3 bone

a t(9;22).

3: Q-bands

and with

to

the

ANLL

respect in leuke-

one

of

the

inv(3)(q21q26), and

abnormal

megakaryocytopoiesis.’5”6’30’3’ Patient I had a high platelet count and numerous micromegakaryocytes in his bone marrow in the blast phase, reminiscent of the findings in ANLL patients with t(3;3) or inv(3). In contrast, patients 2 and 3


T(3;21)

IN BLAST

had low logically phase,

PHASE

1341

platelet counts and a marked identifiable megakaryocytes suggesting

are

3q26

OF CML

that

important

karyocyte

factors

reduction of morphoin the marrow at blast

other

than

in determining A breakpoint

abnormalities.

the

a breakpoint

presence in 3q21,

at

of megarather than

3q26, in the blast phase of CML has been proposed associated with a high platelet count and abnormal karyocytes.

Bernstein

et

secondary cytogenetic time of blast phase like

that

both

seen

had

karyocytes

point

at

findings without

and

platelet time

the

in these

reported

two

counts of blast

cases

in certain

patients

had

numerous

phase.

The

In the

.

had

common

break-

however,

additional

examples

occurring tant site By

at 2lq22,33 with respect

analogy

suggesting to progression

to other

ments in human molecular level,

that

recurring

this may of CML.

are

3q26

and

from

during

of the

chronic

to

3q2626 from

and

patient

2 1q22,27

the chronic at blast than the

gene;

located

farther

for the

conver-

Our

initial

phase.

by standard which have respectively,

1 . By using

of either

basis

blast

has been to determine whether TFRCor ETS2,

bands

2 1q22

the t(3;2l) The latter

primary clone in patients I and 3. Therefore, of this abnormality at the DNA level might

CML

mangements

Southern

been was

this

method,

however,

new

rearranged

we did not find techniques

by which one can may allow detection

away

from

blot

localized

these

such examine of rear-

genes.34

ACKNOWLEDGMENT

We

thank

Dr

morphological

iames

review

W.

Vardiman

of of these

for

cases;

Drs

his assistance Claudio

in the

Schneider

and

Takis S. Papas for supplying the TFRC and ETS2 probes, respectively; Marjorie Isaacson for data management; Paulette Martin, Mary E. Neilly, and Mariann Coyle for technical assistance; Leslee Snyder for photographic assistance; and Elisabeth Lanzl for editonial comment. We thank the following physicians for referring the patients who are included in this study to the University of Chicago: Drs W. D. Pletcher, C. M. Shapiro, S. C. Weil, and i. N. Winter.

be an imporrearrange-

have been studied of the breakpoints

in bands

of the t(3;2l)

absence

as pulsed-field gel electrophoresis, very large regions of DNA,

of CML. observed of eight

chromosomal

leukemia that the consistency

the

abnormalities

needed for confirmation of this possibility. The breakpoint in the t(3;21) at band 21q22 also comesponds to one breakpoint in another specific abnormality found in ANLL, namely, the t(8;21 )(q22;q22).32 The t(8;21) has not been identified in any reported cases Alimena et al, however, tabulated 256 breakpoints during blast phase of CML and found a cluster

genes

for an understanding

of

in DNA

that a breakpoint at band 3q26 may also influence the mega-

cases;

by

t(9;22) in the an investigation

near

the

specific

in patient I and by the presence of the t(3;2I) as the only chromosomal rearrangement other

approach analysis

report,

that

in this rearrangement. Furthermore, an important role in disease progression.

be helpful

micromega-

present

phase phase

sion

a t(3;9)(q2l;q34);

and

is 3q21

to be megawho

implies

participate may play is suggested

involving 3q21 at the had an inv(3)(q21q26)

the other

in patient 1 suggest a 3q21 abnormality

karyocytes

two

abnormalities of CML.’7 One

in ANLL,

elevated

al

t(3;21)

at the in the REFERENCES

I . Rowley chronic

iD:

A new consistent

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