Cancer Genetics and Cytogenetics 132 (2002) 46–50
0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.
PII: S0165-4608(01)00507-6
Philadelphia-positive acute lymphoblastic leukemia with multiple
subclones including duplication of the Philadelphia
chromosome and Abelson oncogene
Roberta La Starza
a
, Antonella Vitale
b
, Anna Serra
c
, Giuseppe Saglio
c
, Giuseppe Fioritoni
d
,
Daniela Falzetti
a
, Massimo F. Martelli
a
, Robin Foà
b
, Cristina Mecucci
a,
*
a
Hematology and Bone Marrow Transplantation Unit, University of Perugia, Policlinico Monteluce, 06100 Perugia, Italy
b
Dipartimento di Biotecnologie Cellulari ed Ematologia, University “La Sapienza”, Roma, Italy
c
Division of Internal Medicine and Hematology, Ospedale S. Luigi Gonzaga, Orbassano, Italy
d
Division of Hematology, University of Pescara, Pescara, Italy
Received 27 February 2001; received in revised form 30 April 2001; accepted 1 May 2001
Abstract
A case of Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) with multiple subclones includ-
ing duplication of the
BCR-ABL1
fusion gene and of the Abelson oncogene (
ABL1
) is reported. Cytoge-
netically, two different rearrangements of chromosome 9 not involved in the t(9;22) were found in two
subclones. In one subclone the normal 9 was lost and replaced by an acrocentric marker, which contained
an additional copy of the
BCR-ABL1
fusion gene. Reverse transcriptase polymerase chain reaction de-
tected the fusion transcripts p210 (e13a2 junction) and p190 (e1a2 junction), whereas fluorescence in situ
hybridization showed the major
BCR-ABL1
junction in both Ph chromosomes, strongly suggesting that the
presence of the p210 and p190 proteins in this case was due to mechanisms of alternative or mis-splicing
at the transcriptional level. The second subclone showed the classic t(9;22) plus an add(9)(p24) containing
two copies of the
ABL1
gene. Other molecular events involving chromosome 9 were a monoallelic loss of
JAK2
in both subclones and an additional loss of
P15/P16
in the subclone with the acrocentric marker
bearing the extra Ph chromosome. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction
Translocation (9;22)(q34;q11) occurs in about 25% of
adult acute lymphoblastic leukemia (ALL). The molecular
consequence of this reciprocal translocation is the juxtapo-
sition of the Abelson oncogene (
ABL1
) from chromosome
9q34 to
BCR
sequences on chromosome 22q11. One-half of
Philadelphia-positive (Ph
ϩ
) ALL express the p190 protein
(e1a2 bcr/abl junction), which is associated almost exclu-
sively with an acute leukemia phenotype, whereas the p210
transcript (b2a2 or b3a2 bcr/abl junction) is the predominant
fusion gene product in chronic myeloid leukemia (CML)
and is also found in rare cases of acute myeloid leukemia
(AML) [1]. No clinical or hematological differences have
been associated with the presence of either the p190 or the
p210 protein [1]. Low expression of p190 mRNA has also
been detected by quantitative polymerase chain reaction
variably in 70% of chronic phase CML, in 80% of CML un-
der interferon-
␣
treatment and in 100% of chronic phase
CML and ALL bearing the p210 fusion transcript [2,3].
Whether the presence of p190 mRNA in p210 positive
ALL plays a role in the pathogenesis of the leukemic pro-
cess is unknown. Mechanisms of alternative or mis-splicing
of the
BCR-ABL
chimeric gene, at the transcriptional level,
have been hypothesized [2,3]. In the case of Ph
ϩ
ALL with
both p210 and p190 hereby described combined cytogenetic
and fluorescence in situ hybridization (FISH) analyses pro-
vided strong indication for the generation of two transcripts
from one or two fusion genes involving only the major
breakpoint region. In addition, a cascade of cytogenetic and
molecular events previously unknown in ALL, such as du-
plication of the Abelson gene in Ph
ϩ
cells and a monoal-
lelic loss of
JAK2
at 9p24, was identified.
2. Materials and methods
2.1. Patient
A 16-year-old girl presented with anemia and throm-
bocytopenia. Clinical examination revealed hepatosplenome-
* Corresponding author. Tel.:
ϩ
39-075-5783808; fax:
ϩ
39-075-
5783691.
E-mail address
: crimecux@unipg.it (C. Mecucci).