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1989 74: 2088-2095

Molecular heterogeneity in acute leukemia lineage switch

GA Gagnon, CC Childs, A LeMaistre, M Keating, A Cork, JM Trujillo, K Nellis, E Freireich and SA Stass

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Molecular
By Gregory Jose A.

Heterogeneity
Gagnon, M. Trujillo, Craig Kevin

in

Acute
Anne Emil

Leukemia
LeMaistre, Freireich, and

Lineage
Michael Sanford Keating, A. Stass

Switch
Ann Cork,

C. Childs, Nellis,

associated genes at conversion Six cases of acute leukemia that underwent lineage switch least one of these lymphoid from acute lymphocytic leukemia to acute myelogenous to acute myelogenous leukemia. The single case (case 3) in leukemia are reported. The mean age of the patients was which there were no lymphoid gene rearrangements at 24 years. time to conversion was 36 months. and survival conversion was also the only case in which independent after conversion was only 3 months. Of the three cases karyotypic abnormalities at diagnosis and conversion were which showed abnormal metaphases at both diagnosis and demonstrated. Our findings suggest that lineage switch conversion. two (cases 2. 5) showed related cytogenetic can represent either relapse of the original clone with abnormalities. and the third showed (case 3) independent heterogeneity at the molecular level or the emergence of a chromosomal changes. Molecular analysis for immuno- second new leukemic clone without molecular heterogeglobulin heavy chain and T-cell receptor $ chain genes neity. showed that five of the six cases had rearrangement of at 0 1989 by Grune & Stratton. Inc.

HE

CORNERSTONE

for

diagnosis

and

lineage

assign-

Striking

lineage was in these true lineage of a

heterogeneity, The suggest of the at new cases relapse second molecular AND that

especially cytogenetic lineage clone molecular original the level. METHODS malignancy

at switch

the and with level without

molecular molecular can or either the lineage accom-

ment in acute leukemia continues to be the light microscopic and cytochemical criteria established by the French-American-British (FAB) cooperative group.4 Lineage switch is the term that leukemias that meet standard (lymphoid or myeloid) at initial the criteria for unique example some among mated acute leukemia AML the Several lineage acute the opposite of the lineage The has been used
FAB criteria

level,
findings

demonstrated.

represent panying emergence heterogeneity

to describe
for a

acute
lineage meet

heterogeneity

diagnosis

but relapse at

at the

lineage.5 Lineage heterogeneity that frequency leukemias

9%#{149}5.6 Most

switch a is exists switch

in

MATERIALS

leukemias.67

of

lineage

patients with acute to be between 6% and lymphocytic (AML) converting switch to leukemia

that relapse reports have to acute However, rare inchildren.

is estibeen cases Most

Patients. One hundred two adults at M.D. Anderson Cancer Center with a diagnosis of acute leukemia relapsed between December 1985 and March 1988. At initial diagnosis, 35 patients had ALL. Five of these patients (14% of adult ALLs that relapsed) and a sixth

(ALL) have been

myelogenous

conversions.585 ALL cases reported have

described.567 occurred

of pediatric of lineage patients aspirate

patient at relapse met FAB different from that documented form the basis of this report.
and cytochemistry/enzymatic

cooperative at initial

group criteria diagnosis.

for a These

lineage
tion may cell that phoid or

mechanisms have been suggested to conversion in acute leukemia. Leukemic

account transforma-

for

Morphology

smears

were

routinely

stained

with

analysis. Marrow Wrights-Giemsa.

Cyto-

stains included myeloperoxidase#{176} (MPO), a-naphthyl occur in a multipotential hematologic progenitor chemical butyrate esterase,2 naphthyl AS-D chloracetate esterase,2 and has the capacity to differentiate along either lymperiodic acid-Schiff. An indirect immunofluorescence technique was myeloid pathways.72 Exogenous factors such as used to identify terminal deoxynucleotidyl transferase (TdT).22 chemotherapy or endogenous changes such as acquired chroCytochemical and TdT staining was graded as follows: <5% mosomal abnormalities could alter the differentiation pro-blasts positive, + 5% to 25% blasts positive, + + 25% to 75% blasts gram of the leukemic cell, leading to a switch in phenotype at positive, and + + + >75% blasts positive.

relapse.9#{176}89 Alternatively, might be the cause of an finding of distinctly different diagnosis present and lineage six cases of switch lineage

a new leukemogenic event apparent switch in lineage. cytogenetic abnormalities supports switch this mechanism.6 from ALL to AML.

Ultrastructural

examination

of

leukemic

blasts

for

myeloperoxi-

dase was performed according to standard methods.23 The sections The on a Jeol I200EX electron microscope at 60 KU. atwere analyzed Immunophenotype. The composite surface immunophenotype We of the leukemic cells was determined with a battery of monoclonal
antibodies according to previously described OKT4(CD4), methods.24 The follow-

ing
From Medicine, Program, Anderson Houston. Submitted Address the Hematopathology Department Division Cancer TX. April reprint 4, 1989; accepted to Gregory June A. 23. Gagnon. 1989. MD, Department requests of Center; of Medicine, and Program. Hematology. The Molecular Division Adult University Diagnostic of Leukemia of Laboratory

FITC-conjugated
OKT3(CD3),

monoclonal

antibodies

were
OKT8(CD8),

used:

OKTll(CD2),

OKMI(CDII) (Ortho Diagnostics, Westwood, MA); Common antigen (CALLA, CDIO), Leu-l(CD5), Leu-I2(CD19), Research ALL (Becton Dickinson Monoclonal Center, Mountain iew, V Texas. M.D.HLA-DR Associates, CA); Bl(CD2O), B4(CDI9), MY4(CD14), MY7(CD13), MY8 and MY9(CD33) (Coulter Immunology, Hialeah, FL). The analysis
was performed on an Ortho Spectrum III flow cytometer (Ortho

Diagnostics) equipped with a 2140 data analyzer which can use of Clinical Pathology and Diagnostic Medicine, East Carolina forwardand right-angle light-scatter characteristics to gate on the University School ofMedicine, Greenville, NC 27858-4354. blast population. Reactivity over background in more than 20% of The publication costs ofthis article were defrayed in part by page the blasts was considered a positive result. charge payment. This article must therefore be hereby marked A direct immunofluorescent technique using FITC-labeled anti-z chain antibody (Kallestead, Austin, TX) determined the advertisement in accordance with 18 U.S.C. section 1734 solely to heavy indicate this fact. presence of cytoplasmic immunoglobulin.25 The percentage of blasts with positive cytoplasmic staining was determined by visualization I 989 by Grune & Stratton. Inc. under a fluorescent microscope. 0006-497i/89/7406-0035$3.OO/O
2088
Blood, Vol 74, No 6 (November 1). 1989: pp 2088-2095

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ACUTE

LEUKEMIA

LINEAGE

SWITCH

2089

1 . Clinical
Mediastinal Mass Splenornegaty +
-

Data
Treatment at Conversion AMSA/HDAC Survival From Conversion (mo) 2 Remission After Conversion No Died

Patient 1

Age/Sex 7/M

Treatment Diagnosis COACP Aase

Time to Conversion (mo) 45

Relapse

(no.)

at Conversion Second

Outcome with leukemia

1+
/+ //+

2 3 4 5 6
Abbreviations: intermediate-

1 6/M 1 9/F 24/F 23/F 55/M

ADOAP. or high-dose

ADOAP
VAD
VAD

63
30
8

Second
First First

HDAC
HDAC HDAC

0.5
12 1 .5

No
Yes No

Died
Died Died

hypoplastic
with with leukemia leukemia

-I-/-

VAD
AMSA/HDAC 60

First
First arabinoside, Aase, cytoxan,

Transplant
IDAC prednisone; oncovin, VAD, cytosine vincristine,

1
1 adriamycin,

No
No deca&on;

Died
Died

with

leukemia

hypoplastic AMSA, amsacrine; I/HDAC,

a&iamycin, cytosine

oncovin, arabinoside;

cytosine COACP

arabinoside,

prednisone,

and

L-asparaginase.

Cytogenetics. marrow cells

niques for

Chromosomal at diagnosis and

culture, harvest

studies relapse.
and staining

were performed on Previously described

were used.2627

bone ALL to AML. tech- morphological

Giemsa-

Lineage criteria.

was etermined d The patients Time months). at the theew n

using standard at diagnosis to conversion In first lineage

FAB were ranged aged from phenoit

to 55 years

(mean

24 years).

banded metaphases were analyzed, and karyotypes were reported 8 to 63 months (mean 36 according to the International System for Human Cytogenetic typic conversion occurred Nomenclature (ISCN I985).#{176} maximum A of 25 metaphases were at the time of examined. Karyotypes were considered related when metaphases at occurred conversion were treated for diagnosis and relapse showed common rearrangements or patterns of chromosome gain similar chromosome
identified. Molecular

four patients, relapse; in two, All patients (AML). Survival

second relapse.

at

or loss. They were considered abnormalities at diagnosis DNA described

unrelated when noafter and relapse were After

conversion conversion,

was 2 patient relapsed

months in but one of the patients. all 3 achieved a 6-month remission but and died with disease. Therapy at conversion is shown in Table The 1 . in four of the six patientsppeared a to The the remaining time of
switch

subsequently
analysis.

from leukemic samples was extracted by previously procedures.29 Restriction enzyme digestion with EcoRI, HindIII, or BamHI (Bethesda Research Laboratories Life Technologies, Gaithersburg, MD) was performed on 10 zg DNA. Digests were electrophoresed on a 0.7% agarose gel, transferred to nylon filters, and hybridized with the following radiolabeled probes: JH, immunoglobulin heavy chain joining region, 6-kilobase BamHI, HindIII fragment (Oncor, Gaithersburg, MD, cases 2, 4, and 6; and Dr Phillip Leder, cases I, 3,5), and and Tcf, T-cell receptor gene cDNA hybridizing to constant regions Cj3l and C$2 (Oncor). After hybridization, filters were exposed to Kodak XOMAT-AR x-ray film at -70#{176}C I to 7 days. for
RESULTS Clinical course and outcome.

initial diagnosis and leukemia at conversion be resistant to had hypoplastic evidence

The five adults

chemotherapy. marrows at
with lineage

two death

patients without
in an ALL

of disease.
occurred

population 1 1 3 patient one lineage

Morphology

with years, switch

a cumulative which case

risk

during

the

study

period

of

is incidence an inthis population of every 22.6 patient years at risk.

analysis.

and

enzymatic

Morphology

and

enzymatic
All patients

analysis

are

shown
negative

in Table and 2
and

were MPO

Figs 1 and 2. TdT positive and diagnosis,

1 through

come

are

shown

inTable

1 . All

Clinical cases were

course and outconversions from

Table 2. Morphology

morphologically appeared to be lymphoid meeting the standard criteria for ALL. were examined by electron microscopy
and Cytochemistry
BM

atinitial
Cases

at

initial

5 diagnosis.

Peripheral Patient WBC x i03/pt.

Blood Blasts (%) Blasts (%) MPO ANBE

TdT

EM

FAB

ID LS 2 ID LS 3
ID

231 103 3.5 28.2

4.4 119

94 8 1 96 80
28 31

83 83 86 96
92 45
--++

+++
-

LV MY/MO
LY

L2 M4
L2

+ + +

Rare
NA
-

+++

+++

++
+
-

MY
+ LV
NA

Ml
L2
M4

Rare
++

LS 4 ID LS 5 ID LS 6 ID
LS

30.8 1.5 67 14.2 0.8

1.5

78 0 88 85 9
14

88 51 95 92 70
87 +++

+++ -

LY MY

L2 M2

+(lO%)

Rare

+++

LY

L2

+ + +

NA

MY

Ml

NA -

+ +++

NA MY

Ll Ml

Abbreviation

5:

NA. not

assessed;

LY,

ly mphoid;

M Y,

myeloid;

MO,

monocytic;

ID,

initial

diagnosis; Ii neage LS,

switch.

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GAGNON

ET AL

Fig 1. Patient 1. Blasts at initial diagnosis showed lymphoid features by light (A) and electron microscopy (B). MPO cytochemical stain was negative. At conversion. the morphology that was of myelomonocytic blasts by light (C) and electron microscopy

(E).

MPO-positive
rows).

granules

were
stain for

evident
MPO

by electron
was positive
(D).

microscopy

(ar-

Cytochemical

absence by was

(Table Cytoplasmic markers

3) was

determined

in

five

cases

at

initial

diagnosis. 4), surface T-

heavy chain and/or were present two in cases

B-cell-associated (cases 3 and

cell-associated type (HLA-DR immunologic in 3) feacells myeloid At lineage

markers in one case (case) andI null phenoonly) in one case (case 6). Case 5 displayed surface features oflymphoid (CD2, CDIO) and CDI3, five CD33) of six lineage. cases displayed at least one switch,

(CDI5,

(case 6) and most instances in and 5) myeloid associated myeloid surface

three or more(cases I , 3, 4, surface markers. In addition to of these cases were also

markers, four

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ACUTE

LEUKEMIA

LINEAGE

SWITCH

2091

-:
:

:
:
6q1

.!#{149}IQ
r

5
. -,

PC

:
.

#i

\f

.4 ..4

Patient 2. At initial diagnosis. the blasts were lymphoid granules were ultrastructurally absent in cytoplasm of blasts (B). At conversion, blasts displayed myeloid morphology by light (C) and electron microscopy (E). MPO stain was positive (D). E (A).

Fig 2. MPO

positive

for

either

T-cell-associated 6)

(cases

3,1, and

5)

or

(cases

3,

4,

and

5).

All

occurred

at

I Iq23-25

but

.1
involved

B-cell-associated displayed a more in more than than

(case pre-B-ceIl of the 90% of the

markers. At phenotype (CDIO, cells and blasts. is shown abnormalities

conversion, 19, 20, MPO-positive in Table were

90%

blast

different reciprocal 2 three Three patients had clg) in and conversion staining diagnosis case cases (cases 2 and

chromosomes, 4, 9, and 10. abnormal metaphases at both (cases 2, 3, and In two 5). karyotypic changes were of these noted

initial

5), similar

at diagnosis and conversion, suggesting a clonal 4. In five in cells Conversely, case 3 showed unrelated karyotypes of six patients identified atrelationship. diagnosis and conversion, suggesting the emergence either initial diagnosis or conversion. Although most of the at initial of a new independent clone at conversion. karyotypes were complex, three cases did include translocaanalysis. Result of molecular analysis is tions that involved a break in the long arm ofchromosome 1 1 Molecular
Cytogenetics.

Cytogenetics chromosomal

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2092

GAGNON

ET AL

Table
Patient Til CD2 T3 CD3 T4 CD4 CD8 T8
CD5

3.

Immunophenotype
Bl CD2O B4 CD19 Slg OKM1 Cig MY4 CD11 MY7 CD14 MY9 CD13 MY8 CD33

LEU1 HLA-DR

CALLA CD1O

ID LS
2
-

+
-

NA NA

NA
-

NA

NA
+ +

NA
+

NA
+

NA

+
NA NA

NA

ID LS
-

NA
-

NA
-

NA
-

NA
-

NA

NA

NA

NA
100%

NA

NA
-

NA

NA

NA

NA

+ NA
+

+ +
-

+ +
-

+ NA
NA

3
ID LS
-

NA NA

NA
+

NA
+

NA
+

NA
+

4
ID
-

+ NA

35% NA

LS 5 ID LS

+ NA NA
NA
-

+ + +
NA
+

+ +

+ -

NA NA

NA NA

+ +

+ +
NA
-

6
ID LS
-

+ + + over

NA +

NA
-

NA
-

Abbreviations:

NA,

not

assessed;

>20%

background; -

<20%

+.

given Tcfl bands Cases ments. netic strated, bands

in Table at conversion. with

JH,

5 and and three

Fig Five

3. All of the showed

cases

were

probed bands
Tcfl

with with
rearrange-

JH and adjacent Tcfl.

identical

with bands.

the lanes,
molecular

JH probe. we on At this

By analyzing the relative analysis, the

the

DNA

on of

the the

same were

gel of

in

six patientsshowed rearranged both and JH in which conversion had with JH and that

rearranged

determined
weight

mobility rearrangements

Based

5 and Case was

6 demonstrated 3, the only case also the only case probed cells from an

independent was Tcfl. demonexclusively

cytogeconfiguration.

conversion.

initial at diagnosis,

diagnosis and lineage the was in gene germline Tcf3 the

abnormalities at conversion

at diagnosis and when

germline DISCUSSION morphologic the lineage

DNA from leukemic switch were available faint germline

initial at patient intense

diagnosis and lineage 5. Both samples showed single rearrangement Table

Standard applied

FAB

and

cytochemical of each case at

criteria diagnosis

band and

were

to assign

4.

Cytogenetics Lineage
23

Patient
1

Initial

Diagnosis
NA

Switch with unrelated clones and cells with

Cells:

45

to 47
additional

chromosomes
changes. XY,
-

Clone

1: 45.

-7.t(3;7)(q27;qll),

t(8;l7)(pll;p13) del

Clone 2: 45,X,
del(

Y,del(

1 )(p22p34),

( 1 1 )(p 1 1 p 1 5),t(
1 9)(p 1 3),t(2

1 6;?)(q23;?).
1 ;?)(q22;?)

2CeIls: 2 5 Abnormal metaphases with 46 to 47 chromosomes 1 5 Cells:

1 Cell:

46.XY 47,X,
46,XY

+ X. -

Y,

5,

8,

8,

1 2,

18,

del(9)(p

1 3p22),t(9;

1 2)(p24;ql

3)

3 4

1 1 Cells: 2 Cells: Insufficient

46,XXX 46,XX,i(7q),?t(14;l9)(q23;pl3) metaphases

20 Cells: 4 Cells: 1 5 Cells:

1 0 Cells:

46,XX,del(6)(q23q27),t(9; 46,XX.t(9;l 46.XX

1 03-1 t(4;l 07 chromosomes

1 l)(p22;q25)

l)(p22;q25)
with related clones and

l)(q21;q23)

1 1 6

Cells: Cells:

46,XX,t( 45,XX,
-

1 0; 1 1 )(p 1 5;q23) 5,
1

1 8 Cells: 7 Cells:

4 1 to 47 68 to 88

chromosomes chromosomes

with with

related related

clones clones

9,t(4;?)(p

1 6;?),
lpl3),

t(l0;l

l)(pl5;q23),del(l7)(pl

mar

6 Cells: 6 Cells:
5 6 1 2

46,XX 43 to 45 chromosomes polyploid with related clones Abnormal 46,XY metaphases

Chromosome

abnormalities

similar

to those

reported

at diag-

nosis, ie, t( 1 0; 1 1 )(pl 5;q23). Insufficient yield of analyzable metaphases

Cells: Cells:
NA,

Abbre

viation:

not

assessed.

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ACUTE

LEUKEMIA

LINEAGE

SWITCH

2093

Table

5.

Molecular

An alysis

for
JH

Lymphoid Genes

at Conversion
Tc9 R G
G

and/or

Tcf3 case with negative.

gene
This

rearrangements was germline

is of interest

at conversion, at conversion in view (case of the

whereas 3) was association

the also of

Patient 1 2
3

only TdT TdT

that gene
whose

G R
G

rearrangements.3435 leukemia
coexpress

Acute
leukemia more switch

mixed-lineage
blasts than

has been relationship

described between

as acute
markers of

4 5* 6 Abbreviations: ldentical conversion

H

R R R G. germline. R, rearranged. was present at initial

G R R

differentiation

one acute
of

lineage.36 of lineage
mixed

The

lineage Howleukemias
suggesting

and
were

mixed-lineage
lineage

leukemia switch
at

isuncertain.6 arise from

diagnosis,

ever,
diagnosis and

some cases lineage

leukemia.

may
initial

rearrangement

that

(described

in the

Results section).

that
mixed

switch
An and levels for

may

be part
of

of the
this criteria

biologic
is patient at light

spectrum
5 who and ultra-

of
met

example

and

relapsed

relapse.3 as

All AML.
reported

cases were This is

cases of

initially consistent
lineage

diagnosedas ALL and with most the of

switch, which are

morphologic structural also immunophenotype bodies

cytochemical

the panel

diagnosis including staining the

the

of ALL, several with mixed

blasts

but an these

expanded antiof myeloid-asso-

previously conversions leukemia

antimyeloid

from ALL

to AML.585 distinguishable microscopy

Undifferentiated

acute

showed markers,
leukemia. surface

positive
At

subtype
alone.23303 tiated

may not be easily L2 by light

At the leukemias display

from ALL FAB and cytochemistry

many undifferen-

ciated
this myeloid expressed

demonstrating
relapse, antigens

lineage nature patient of 5 retained addition, in the theynow featuresof setting

is not

ultrastructural

level,

and switch

CD5. and
the leukemias.

In

MPO of our typical

granules cases examined lymphoid

and

are features

actually such

the Although
mixed-lineage restricted

morphologic lineage
to mixed leukemia,

cytochemical can occur

An phenomenon expanded

myeloid ally In ules

peripheral

leukemias.

All displayed

ultrastructur-

AML. asacute
sarily

of
necesof

at diagnosis addition, was is an cases

been

heterochromatin

the absence confirmed. enzyme ofALL.22

demonstrated

and few cytoplasmic organelles. of MPO-stained cytoplasmic granpresent in the majority of lymphoblasts However, itis not restricted to ALL,
in up 10% to

panel

six
phoid no

myeloid-associated
blasts at initial evidence

antibodies
diagnosis in

failed
patient

to react
4. In

to the
this

lymyet

instance,

TdT in most
having

for
conversion

mixed
between

lineage
at T-cell switch

was
relapse.

present
features

at diagnosis, ALL in and

the

lineage

occurred

of AMLs.3233 positive TcIT

display cases

All staining

of

Associations occurrence of

our
in

lineage-switch
more than
75%

cases of
cases

demonstrated the blasts

continued percentages.

lineage

have

been

reported.59#{176}37 Three

at
to

initial
These

diagnosis.
TdT-positive

At of the patients typic

and/or

we studied at

displayed

T-cell-associated diagnosis In addition, (cases patient

pheno1 and I at 5)

conversion, blasts, but

three

markers
conversion

in decreased

had JH also

either initial (cases 3 and 5).

Case
TcB
I

Case H

Case H

4 H
l I

Case

6 TcB

-24
11-.-

20-

4
-11 20-11
H
-

20-1
-11

-7.7

4.2-3-7

Barn HI Eco RI
.

Hind

III

ECO Hind
patients ,

RI

Hind

III

EcoRl
Fig 3. Molecular

HindU
analysis of blasts

ECO RI
from

III 2. 4. and 6 at the time of conversion 1

are shown by a long bar with

to AML.
corresponding

Rearrangement
molecular

of H and/or
weight.

Tc
Short

was
bars mark

evident in each crosshybridization

case
artifact.

(arrows).

Germline

bands

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2094

GAGNON

ET

AL

initial diagnosis had cell count, suggesting

a mediastinal mass high and T-cell immunophenotype. arise they level

of the

white

blood These

revealed cases rangements rangements two cases. in AML.

unexpected

heterogeneity.

Four

cases

had

rearin

of lineage
progenitor.5 regulation studies question.
A striking

switch and at the

may expression molecular

from may are

a common be the necessary

T-cell/myeloid result genes. to In-depth resolve

of the immunoglobulin of the Tcfl gene.

Rearrangements of JH

gene, and three had rearBoth genes were rearranged

and Tcfl have been reported

Alternatively,

of altered this

of lineage-related

Raghavachar the same

H

et al3

report was

the

conversion at diagnosis

of an

acute
which and

undifferentiated
conversion. patient 5 at
rearrangement.

leukemia
rearrangement Gene diagnosis
This

to a monocytic
identified studies conversion of the
findings is described

leukemia
performed
in greater

in
on an

example

immunophenotypic

heterogene-

rearrangement and presence

cytogenetic patient

ity

that

can time in

be noted marker more

with results

lineage obtained to AML.

switch Even blast clg) and antibody

is illustrated of patient was than though PO M cells, was that apparent same have with ore m aberrant presencef o leukemic been

by theour detail
as

demonstrated same
at

immunologic
2 at the

on theblasts the

identical

of conversion than (CD2O, blasts supports lymphoid lymphoid

and

elsewhere.49
as similar

The the

rearrangements
diagnosis and

positive 90% unusual

90% 19, for the

of 10,

a pre-B-cell found.

well

immunophenotype positive case might and

conversion This morphologic gene and

which nosis

support
switch

clonal

nature

of these

cases despite

a for JH one in at diag3 patient

each

in lineage.

contention for in the the features

One

expression
myeloid cell
19,36,38

be responsible

patient (patient Tcfl at conversion. independent

and conversion

3) in our This case

were found.

series was germline was also the only changes

In addition,

abnormal and
cases

chromosome for
series

Certain ciated which can Cases also with appear

myeloid chromosome prognostic clonal

leukemias

assomany

achieved ofNone
sion. of

a remission
the other

survived
in our

I year
achieved

after

conversion.
remission after

specific to have to assess

abnormalities, significance.39 Cytogenetics relationships

conversion
In

and
contrast,

none
in

lived acute directed

longer

than
report5

2 months
ofsix

after

converremission at conver-

be used

in leukemias.#{176} abnormalities at lineage switch repreclone. Alternatively, abnormalities at diaga new clone representing been asso-

a previous

pediatric patients

2 and 5 had related chromosomal diagnosis and relapse, suggesting that sented a relapse of the same leukemic the
nosis

with with
sion.

lineage

switch

leukemia, toward

four the

achieved phenotype

chemotherapy

finding

of independent

karyotypic

was second ciated

extend Three

and conversion, responsible for acute with

this of

as in case the relapse, transformation.

3, suggests that perhaps 1 q have

Our data suggest that some cases of lineage switch represent a relapse of the original leukemic clone with morphoa logic conversion. Lineage switch acuteeukemias l that arise through geneity this mechanism with lymphoid to AML. indicate
switch at

leukemic lineage
observation

Translocations

involving

chromosome

appear to exhibit molecular heterogene rearrangements persisting one some of our instances cases and previous leukemia leukemic that rearthe

at

heterogeneity in the the

in

in acute context of details

commitment

leukemia.3843 We conversion lineage switch. reports6

involvlineage

However, that in represent

acute of a new

the cases its

we report
role

displayed

translocations

may
initial

emergence

ing tion

I 1q23

to 25. Once

molecular
lineage

ofthis
and

region
differenta-

are clone
observed rangements

characterized

established,

in acute leukemia may become evident. Studies of these cases at the time of lineage conversions with the lymphoid-associated gene probes JH and Tc/3

mechanisms acute leukemia

by a different diagnosis without at conversion to AML. of lineage commitment

will help

morphology from lymphoid gene Further studies of and differentiation lineage switch.

in

us understand

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