overview [molecular diagnostics | cytology | hematology]
Clinical Significance of Cytogenetics in
Acute Leukemias
Jigar Shah, MD,1 Karl Theil, MD,2 Matt Kalaycio, MD1
1Department of Hematology and Oncology, 2Department of Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, OH
DOI: 10.1309/03CVN1JH4DA08M5M
왘 The majority of acute leukemias
harbor genetic abnormalities that can
be visualized by cytogenetic analysis.
왘 A plethora of evidence indicates that
these aberrations represent critical
early steps in a process that leads to
the disruption of hematopoiesis and
the development of leukemia.
In the past decade, karyotype analysis
of leukemic cells has improved our under-
standing of acute leukemias. Cytogenetic
studies of human leukemias have illustrated
that a large proportion of patients display
acquired clonal chromosomal aberrations.
Additional study of these aberrations led to
molecular analyses allowing identification of
genes implicated in the pathogenesis of
leukemias. Chromosomal aberrations have
also redefined the classification of acute
leukemia and serve as prognostic indicators.
The World Health Organization
(WHO) classification of hematopoietic
and lymphoid neoplasms was recently
published.1 The WHO classification em-
phasizes the basic principle of utilizing
morphologic findings and incorporates
genetic, immunophenotypic, biologic, and
clinical features to define specific disease
entitites. In the WHO classification, recur-
ring clonal cytogenetic abnormalities are
considered diagnostic of acute leukemia
regardless of blast percentage. This review
presents current information on cytoge-
netic findings in acute leukemias and de-
796 fines the association of karyotype, clinical
features, and natural history.
Acute Myeloid Leukemia (AML)
Core-Binding Factor Leukemias
t(8;21)(q22;q22) AML: t(8;21) is
present in approximately 7% of adult de
laboratorymedicine> november 2003> number 11> volume 34
novo AML but is rare in AML patients
>60 years of age.2 This translocation re-
sults in the fusion of the AML1(CBFα)
gene on chromosome 21 to the ETO
(eight twenty-one) gene on chromosome
8.3-5 Although the mechanism of transfor-
mation by AML1/ETO is not completely
understood, one theory suggests that the
AML1/ETO fusion protein dominantly
inhibits the ability of AML1 gene to di-
rect normal maturation and development
of hematopoietic cells.6 In AML patients
with t(8;21), the marrow histology is
FAB M2 in >90% of cases, although oc-
casional patients may have FAB M1 or
M4 morphology.7,8
Frequent morphologic features of
t(8;21) AML include thin Auer rods, bone
marrow eosinophilia, abnormal granu-
lopoiesis including hypogranularity, and
the pseudo-Pelger-Huet abnormality.9
Acute myeloid leukemia with t(8;21) typ-
ically expresses high levels of CD34,
human leukocyte antigen (HLA), HLA-
DR, and may aberrantly express the B
lineage marker CD19.10 Additional cyto-
genetic abnormalities often involve loss
of a sex chromosome, deletion of 9q21-
22, and trisomy 8.11
In general, AML characterized by
t(8;21) carries a favorable prognosis with
appropriate treatment. A Cancer and
Leukemia Group B (CALGB) study
showed that the use of high-dose cytara-
bine (HiDAC) was associated with im-
proved outcomes in patients with CBF
leukemia.12 Acute myeloid leukemia pa-
tients with t(8;21) in particular benefit
from repetitive cycles of HiDAC.13
Factors associated with poor
outcome in t(8;21) AML include older
age,14 lower cytarabine dose,12
extramedullary leukemia (EML),17 CD56
positivity,15 and high white blood cell
©
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(WBC) count.16 Acute myeloid leukemia
with t(8;21) is associated with EML espe-
cially when the blasts express CD56.17 In
a recent study, t(8;21) patients with blasts
expressing CD56 had a significantly
shorter CR duration and OS than patients
with no CD56 expression.15 The presence
of granulocytic sarcomas, especially
paraspinal masses, at diagnosis in
patients with t(8;21) AML is a negative
prognostic factor at least after standard
induction chemotherapy and no site-di-
rected treatment.17
inv(16)(p13q22) and t(16;16)(p13q22):
Acute myeloid leukemia with inv(16) or
t(16;16) occurs in 10% of adult de novo
AML. These translocations result in the
fusion of the CBFβ subunit at 16q22 to
the smooth muscle myosin heavy chain
gene (SMMHC, MYH11) at 16p13.18,19
CBFβ is the heterodimeric partner of
AML1, and together forms the transcrip-
tion factor designated as CBF. Although
the mechanism of transformation by
CBFβ-MYH11 is not completely under-
stood, the fusion protein may also act as a
dominant negative inhibitor of AML1
function. Most cases of inv(16) AML
have French-American-British (FAB)
classification M4Eo morphology,
although rare cases with FAB M1 mor-
phology have been reported.9,20 An
increased percentage of immature
eosinophils are found in most patients
with inv(16) AML with a mixture of
eosinophilic and basophilic granules in
their cytoplasm.21 The basophilic gran-
ules are larger, more irregular, and nu-
merous than in normal immature
eosinophils. The characteristic
immunophenotype in inv(16) AML pa-
tients includes high CD13 positivity and
increased expression of CD2, CD11b,
CD11c, CD14, CD33, CD36, CDw65,
TdT, and HLA.22 Acute myeloid leukemia
M4 with CBFβ-MYH11 has also been
reported to express CD34 and CD117.23
Several reports have demonstrated
that a number of AML-M4 patients origi-
nally thought to have trisomy 22 (+22) as
a sole chromosomal abnormality had in
fact an undetected inv(16)(p13q22) as the
primary aberration.24-26 Trisomy 22 can
be found either as the sole additional ab-
normality or together with other changes
in about 40% of the cases of AML with
inv(16).24 Trisomy 22 is the most com-
mon secondary cytogenetic abnormality
in patients with inv(16) but is rare in pa-
tients with other primary aberrations.27
The correlation of FAB M4 AML with
inv(16) may be higher than reported as it
is likely that cases initially found to have
a sole +22 may also harbor an undetected
inv(16)(p13q22). The presence of +22
should alert the cytogeneticist and molec-
ular biologist to the possibility of inv(16),
the latter being of important prognostic
significance in management of AML.
Acute myeloid leukemia patients
with inv(16) have a relatively high risk of
central nervous system (CNS) leukemia.
The CNS is also a frequent site of relapse
in these patients. In 1 report, 33% of
AML patients with inv(16) had CNS
leukemia at diagnosis compared with 5%
of patients with other types of AML.28 In
another report, 35% of AML patients
with inv(16) relapsed in the CNS at a me-
dian of 19 months.29 Central nervous sys-
tem relapses, however, appear less often
in patients treated with HiDAC.
Large clinical trials have revealed
that CBF leukemia patients, including
those with rearrangements of CBFβ, have
an excellent CR and 5-year survival rates
[T1]. These studies demonstrate superior
treatment outcome of CBF AML, with
>50% of patients still in CR after 5 years,
compared with 32% and 15% for patients
with a normal karyotype or other kary-
otypes, respectively.12,30
Retinoic acid receptor (RAR)
leukemias: t(15;17)(q22;q12) is invari-
ably associated with acute promyelocytic
leukemia (APL), FAB M3, and accounts
for 15% of AML in adults <45 years of
age. t(15;17) results in the fusion of the
promyelocytic leukemia (PML) gene on
chromosome 15 to the retinoic acid re-
ceptor alpha (RARα) gene on chromo-
some 17.34 Rare APL variants include
PLZF/RARα fusion [t(11;17)(q23;q12)],
NPM/RARα fusion [t(5;17)(q23;q12)],
NuMA/RARα [t(11;17)(q23;q12)], and
STAT5b/RARα (interstitial chromosome
17 deletion), but all cases of APL appear
to involve the transcriptionally active,
RARα gene.
The PML/RARα fusion protein acts
as a dominant negative inhibitor of RARα
function.35 In the absence of retinoic
acid, RARα/RXR-α heterodimers inter-
act with N-CoR (nuclear corepressor)
leading to transcription arrest. Transcrip-
tional repression is achieved through the
recruitment of histone deacetylase
(HDAC), thus inducing histone deacety-
lation rendering chromatin inaccessible to
basal transcription machinery.36 All-trans
retinoic acid (ATRA) releases the N-
CoR/HDAC complex and allows active
transcription to resume. All-trans retinoic
acid overrides the dominant negative in-
hibition of RARα by PML/RARα by re-
generation of nuclear bodies with proper
relocalization of PML and release of
HDAC, thus facilitating leukemic cell
differentiation.
Most patients with APL have multiple
Auer rods, hypergranular blasts, and labo-
ratory evidence of disseminated intravas-
cular coagulation (DIC). Hypogranular
variants without Auer rods also exist and
may be confused with monoblasts. Both
hypo- and hypergranular variants are
strongly myeloperoxidase positive, making
the distinction clear cut. Disseminated in-
travascular coagulation is present in 70%
Large Clinical Trials of CBF AML
Study Patients, N
t(8;21)
Grimwade30 122
Groupe Francais de 148
Cytogenetique
Hematologique31
Bloomfield12 84
Schoch32 51
inv(16)
Grimwade30 57
Marlton33 54
Bloomfield12 103
Abbreviations: CR – complete remission, med – median, mo – months, yr – years
© laboratorymedicine> november 2003> number 11> volume 34
to 90% of APL patients at diagnosis or
shortly thereafter. The hemorrhagic com-
plications of APL may be due to increased
fibrinolysis.37 Overexpression of annexin
II by APL cells in patients with t(15;17)
increases plasmin generation by t-PA
thereby contributing to the hemorrhagic
diathesis of APL.37 All-trans retinoic acid
significantly reduces cellular expression of
annexin II and plasmin generation. All-
trans retinoic acid also seems to normalize
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plasma levels of fibrinogen and α2-plas-
min inhibitor, thereby treating the hemor-
rhagic diathesis in APL patients with
t(15;17).37 Bleeding typically begins to
resolve within 5 to 7 days in APL patients
after the start of treatment with ATRA.
All-trans retinoic acid alone induces
remissions in patients with APL, but is not
by itself curative. In APL patients, ATRA
improves OS and event-free survival
(EFS) when combined with conventional
chemotherapy (CT).38 Randomized trials
demonstrate that the addition of ATRA to
CT increases OS and reduces relapse risk
compared to treatment with CT alone.38-40
Several studies have now revealed that
ATRA plus anthracycline as an induction
treatment produces as good a result as
ATRA plus standard CT, implicating a
lack of benefit of cytarabine in t(15;17)
APL.41-43 In contrast to other AML sub-
types, APL appears to respond more to
anthracyclines than to cytarabine.44-47
The less common APL variants har-
boring t(11;17)(q23;q12) or STAT5b/
RARα appear to be resistant to ATRA ther-
apy. Recent preclinical data indicate a po-
tential beneficial role of arsenic trioxide in
ATRA resistant APL.48-50 Arsenic trioxide
CR, % Survival, %
T1
98 69 (5yr)
91 24 (5yr) 797
89 50 (5yr)
92 52 mo med
88 61 (5yr)
90 43 (2yr)
85 55 (5yr)
 appears to cause cell apoptosis at higher
concentrations, independent of the retinoid
pathway, and causes leukemic cell differen-
tiation at lower concentrations.51 Currently,
arsenic trioxide is the treatment of choice
in relapsed APL, particularly in patients
exposed to ATRA within the preceding 12
months. The role of arsenic trioxide as
part of the post-remission phase of treat-
ment is currently being studied.52
The reverse transcriptase-polymerase
chain reaction (RT-PCR) has been an ef-
fective method to detect minimal residual
disease (MRD) in APL patients in CR.53
The majority of APL patients have unde-
tectable PML/RARα by RT-PCR after in-
tensive chemotherapy. However, a
negative PCR does not guarantee the ab-
sence of relapse.54 A positive RT-PCR for
PML/RARα after chemotherapy reliably
predicts subsequent hematologic relapse,
whereas repeatedly negative results have
been shown to be associated with long-
term survival in most patients.55
Other Leukemias
Trisomy 8 (+8): Trisomy 8 is the
most frequent numerical aberration in
AML. As a solitary aberration, +8 is
found in 10% of adult AML but is present
with other abnormalities in another 10%.
Trisomy 8 is most commonly associated
with FAB M1, M4, and M5 morphologies
(in that order of frequency). Patients with
+8 tend to have a slightly older age at
presentation, lower WBC, and lower per-
centage of peripheral blasts.56 A South-
west Oncology Group (SWOG) study56
assessed the impact of +8 on clinical
presentation, treatment response, and sur-
vival in AML. Wolman and colleagues57
demonstrated that OS for AML patients
with trisomy 8 as a sole aberration was
similar to the OS of AML patients with
normal karyotype. Acute myeloid
leukemia patients with trisomy 8 in addi-
tion to CBF cytogenetic changes have
798 better OS.56,57
MLL gene involvement (11q23) in
AML: MLL, also referred to as ALL-1,
HRX, or HTRX1, was first identified in
1991 at 11q23 by Zieminvan der Poel and
colleagues.58 The function of the MLL
protein is yet to be completely
understood; but by direct interaction with
laboratorymedicine> november 2003> number 11> volume 34
DNA or with other DNA-binding
proteins, it appears to act as a transcrip-
tion factor in regulation of differentiating
pathways.59,60 11q23 translocations have
been described in acute lymphocytic
leukemia (ALL), AML, and lymphoma,
and account for 5% to 7% of adult de
novo or secondary AML cases. In
leukemia patients previously treated with
topoisomerase II inhibitors, the 11q23
translocation is identified in as many as
80% of patients.61 Therapy-related AML
tends to occur after a median of 30 to 34
months following topoisomerase II in-
hibitor exposure; and in contrast to
leukemias caused by exposure to alkylat-
ing agents, AML secondary to topoiso-
merase II exposure presents as overt
leukemia without a preexisting MDS.
The most common of the 11q23
translocations is the t(9;11)(p22;q23) in
adult AML, frequently associated with
acute monoblastic leukemia. t(9;11) cre-
ates the MLL-AF9 fusion protein. Mrozek
and colleagues62 suggested better CR
rates, EFS, median survival (MS) in
t(9;11) AML as compared to other 11q23
AML [T2]. This CALGB study also
demonstrated that a higher percentage of
patients with t(9;11) maintained continu-
ous CR when treated with HiDAC or bone
marrow transplant as opposed to those pa-
tients treated with lower dose cytarabine
who tended to have frequent relapses.
Molecular studies have indicated that
the MLL gene is rearranged more
frequently than is revealed by
conventional cytogenetic studies.63 A par-
tial tandem duplication of MLL gene has
been reported in a few patients with nor-
mal karyotype. Newer molecular
techniques such as fluorescence in situ
hybridization (FISH) and RT-PCR may be
required to identify these specific cytoge-
netic abnormalities.
t(9;11) Versus t(11q23): A Comparison of CR, EFS, MS
Outcome t(9;11)
CR, % 79%
Med CR duration 10.7 mo
Med EFS 6.2 mo
MS 13.2 mo
Abbreviations: CR – complete remission, med – median, mo – months, EFS – event free survival, MS – median survival.
From Mrozek K. Blood. 1997;90:4532-4538
©
Monosomy 5 (-5), del(5q),
monosomy 7 (-7), and del(7q) along with
complex karyotypes have been shown to
occur frequently in an older patient popu-
lation, usually preceded by a preleukemic
MDS.64 Loss of 5q and/or 7q has also
been noted to occur in high frequency in
therapy-related AML and MDS due to
alkylating agents and/or radiation therapy,
and less often in de novo disease. These
cytogenetic abnormalities can be found in
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essentially any FAB subgroup. Auer rods
are typically absent with -5, del(5q), and
del(7q) AML.65 Very low CR rates (20%)
were noted in -7 and del(7q) AML, and
in those patients with the coexistence of
chromosome 7 abnormalities with -5 or
del (5q) at the Fourth International Work-
shop on Chromosomes in Leukemia
(4IWCL).66 Monosomy 7 is associated
with hepatosplenomegaly, diabetes
insipidus, fever, and infections.67 Intensely
treated patients with -7 or del(7q) have
been shown to achieve high CR rates but
with short median CR durations.
Prolonged continuous CRs are relatively
uncommon in patients with -5, del(5q), -7,
del(7q), and complex karyotypes.66
Younger patients with these poor progno-
sis karyotypes should be treated with bone
marrow transplantation (BMT).
Acute Lymphoblastic Leukemia
t(9;22)(q34;q11.2): A shortened
chromosome 22 resulting from a recipro-
cal translocation involving the c-ABL gene
from chromosome 9 and the BCR gene on
chromosome 22 with resultant hybrid
BCR-ABL gene on the derivative chromo-
some 22 constitutes the Philadelphia (Ph)
chromosome. The Ph chromosome was the
first chromosomal abnormality to be as-
sociated with a specific malignant disease
in humans. It was discovered in 1960 by
Nowell and Hungerford68 as a distinct
t(11q23) P
T2
57% 0.13
8.9 mo 0.02
2.2 mo 0.009
7.7 mo 0.009
chromosomal abnormality in chronic
myeloid leukemia (CML). In 1970, Propp
and Lizzi69 reported the first case of ALL
with classic Ph in a high percentage of
marrow cells. The Ph chromosome is ob-
served cytogenetically in 95% of CML
cases, 1% to 2% AML cases, 5% of chil-
dren, and 15% to 30% of adults with ALL.
It is the most common cytogenetic abnor-
mality in adult patients with ALL.70,71
Breakpoint locations on chromosome
OS was only 9.2 months for those who
had CR, compared to only 3.6 months for
non-responders.79 Furthermore, the time
to progression overall was only 2.2
months. Therefore, imatinib may have
benefit for rapid control of relapsed dis-
ease, but the response will not be
sustained and allogeneic stem cell trans-
plant (SCT) is required for cure.
Allogeneic SCT is indicated in
younger patients with Ph positive
ALL.78,80 Relapse rates after SCT tend to
be high ranging from 40% to 80% and
disease recurrence after SCT tends to
have a particularly poor prognosis in
adults.78,80 A different clinical behavior
has been demonstrated for Ph positive
ALL expressing p190BCR-ABL compared

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9 appear consistently at the 5’ of ABL
exon a2, whereas several breakpoint clus-
ter regions have been identified along the
BCR gene on chromosome 22. Depend-
ing on which breakpoints are involved on
chromosome 22, various-sized segments
from the BCR gene are joined with the
ABL gene subsequently resulting in
chimeric protein products with variable
molecular weights and presumable func-
tion (p190, p210, p230). The p190BCR-ABL
is predominantly associated with ALL,
while p210BCR-ABL is mostly associated
with CML. The p190BCR-ABL is a more
active tyrosine kinase than p210BCR-ABL
and is found to be expressed in 80% of
pediatric ALL cases, as opposed to only
50% of Ph positive adult ALL cases.72,73
Ph-positive adult ALL patients tend
to be older, with higher WBC and blast
counts and more frequent lymphadenopa-
thy and splenomegaly than Ph negative
patients.74-76 These patients tend to have a
pre-B phenotype. Ph positive ALL pa-
tients have been found to have increased
expression of CD10 [common ALL anti-
gen (CALLA)]. In CD10 positive cases,
BCR-ABL identifies a group of patients
with short remission duration and poor
disease free survival (DFS).77 Even with
intensive chemotherapy programs, Ph-
positive ALL has a dismal prognosis in
children and adults with short remission
duration and survival times.
Cellular proliferation of BCR-ABL
positive ALL cells can be inhibited selec-
tively with a selective inhibitor of the Abl 799
tyrosine kinase, imatinib mesylate.78 A
phase II trial recently evaluated imatinib as
a single agent in relapsed Ph positive ALL.
The results indicate that 29% of Ph posi-
tive ALL patients achieve a hematologic
remission while 17% obtain a complete
cytogenetic remission. However, median

© laboratorymedicine> november 2003> number 11> volume 34

 Clinical Outcomes for Patients with t(4;11)(q21;q23)
Outcome UKALL XA Adults82
CR 70%
MST NA
MDFS 4 mo
DFS 24% at 3 yr
Abbreviations: CR – complete remission, MST – median survival time, MDFS – median disease-free survival, DFS –
disease-free survival, mo – months, yr – years, NA – not applicable, UKALL XA – United Kingdom Acute Lymphoblastic
Leukemia XA, TIWCL – the Third International Workshop on Chromosomes in Leukemia
with p210BCR-ABL in Ph positive ALL pa-
tients treated with SCT. In patients
treated with SCT for Ph positive ALL,
Radich and colleagues80 noted detection
of BCR-ABL by RT-PCR after SCT corre-
lated with a high risk of relapse. The ex-
pression of p190BCR-ABL was associated
with higher risk of relapse than was the
expression of p210BCR-ABL.
t(4;11)(q21;q23): First described in
1977, t(4;11)(q21;q23) is observed in
>60% of infants (<6 months of age) with
ALL, 2% of children with ALL, and 3% to
6% of adults with ALL. The t(4;11) results
in fusion of the MLL gene on chromosome
11q23 to the AF4 gene on chromosome
4q21 forming an MLL/AF4 fusion gene.
An association with B-cell lineage, young
age (<2 years), female sex, high WBC,
organomegaly, and CNS involvement has
been demonstrated with t(4;11) ALL.81 The
immunophenotype is positive for TdT,
HLA-DR, and CD19, and often CD10 neg-
ative. Myeloid antigens, such as CD13,
CD15, or CD33 are frequently coexpressed
in this patient population.81
t(4;11) ALL has a poor prognosis in
both adults and children. Several large
scale trials have demonstrated poor OS and
median disease free survival in patients
with t(4;11) [T3]. Overall survival can be
improved by applying intensive therapy to
such cytogenetic groups that formerly had
been defined as poor risk due to an unfa-
vorable response to standard treatment.85
800 Conclusion
The majority of acute leukemias har-
bor genetic abnormalities that can be visu-
alized by cytogenetic analysis. A plethora
of evidence indicates that these aberra-
tions represent critical early steps in a
process that leads to the disruption of
hematopoiesis and the development of
laboratorymedicine> november 2003> number 11> volume 34
TIWCL Adults83 TIWCL
T3
Children84
50% 88%
7 mo 9 mo
2 mo 5 mo
0% at 5 yr 0% at 5 yr
leukemia. Associations have been
reported between many non-random chro-
mosomal rearrangements and
morphologic and immunophenotypic
characteristics of the leukemia cells.
Karyotypic changes provide important
prognostic information independent of
other variables allowing favorable, inter-
mediate, and unfavorable risk patients to
be distinguished at the time of diagnosis.
The Medical Research Council,30 the
United States Intergroup,30,86 and
CALGB12 trials have clearly
demonstrated superior 5 year OS ranging
from 56% to 65% for CBF and RARα
leukemias, compared with 5 year OS of
12% to 26% for those patients with AML
and other cytogenetics.
Cytogenetics plays an important role
in assessing MRD status and subsequent
prognostication. Persistently positive RT-
PCR for PML/RARα after consolidation
reliably predicts subsequent hematologic
relapse. In ALL patients, the pre-BMT
MRD status has predictive value for post-
BMT relapse-free survival.87 This has led to
risk-adapted therapy where treatment is
tailored according to risk groups; and inten-
sive therapy approaches, including BMT,
are reserved for patients that by virtue of
their cytogenetic profile, may otherwise do
poorly with chemotherapy. In addition to
being a prognostic tool, cytogenetic analy-
sis should provide a better understanding
of the molecular biology of leukemias.
Investigation into mechanisms by which
non-random cytogenetic changes occur and
lead to leukemogenesis is of utmost impor-
tance for tailoring future therapies.
1. Jaffe ES, Harris NL, Stein H, et al. World Health
Organization classification of tumours: Pathology
and genetics of tumours of haematopoietic and
lymphoid tissues. Lyon, France: IARC Press; 2001.
©
2. Sakurai M, Swansbury GJ. Fourth International
Workshop on Chromosomes in Leukemia, 1982:
Overview of association between chromosome
pattern and cell morphology, age, sex, and race.
Cancer Genet Cytogenet. 1984;11:265-274.
3. Nucifora G, Birn DJ, Erickson P, et al. Detection
of DNA rearrangements in the AML1 and ETO
loci and of an AML1/ETO fusion mRNA in
patients with t(8;21) acute myeloid leukemia.
Blood. 1993;81:883-888.
4. Nisson PE, Watkins PC, Sacchi N.
Transcriptionally active chimeric gene derived
from the fusion of the AML1 gene and a novel
gene on chromosome 8 in t(8;21) leukemia cells.
Downloaded from https://academic.oup.com/labmed/article-abstract/34/11/796/2657281 by guest on 20 May 2020
Cancer Genet Cytogen. 1993;66:81.
5. Erickson P, Gao J, Chang KS, et al. Identification of
breakpoints in t(8;21) acute myelogenous leukemia
and isolation of a fusion transcript, AML1/ETO,
with similarity to Drosophila segmentation gene,
runt. Blood. 1992;80:1825-1831.
6. Meyers S, Lenny N, Hiebert SW. The t(8;21)
fusion protein interferes with AML-1B-dependent
transcriptional activation. Mol Cell Biol.
1995;15:1974.
7. Berger R, Bernheim A, Daniel M, et al. Cytologic
characterization and significance of normal
karyotypes in t(8;21) acute myeloblastic leukemia.
Blood. 1982;59:171-178.
8. Swirsky DM, Li YS, Matthews JG, et al. 8;21
translocation in acute granulocytic leukaemia:
Cytological, cytochemical and clinical features.
Br J Haematol. 1984;56:199-213.
9. Arthur DC, Bloomfield CD. Partial deletion of the
long arm of chromosome 16 and bone marrow
eosinophilia in acute nonlymphocytic leukemia: A
new association. Blood. 1983;61:994-998.
10. Kita K, Nakase K, Miwa H, et al. Phenotypical
characteristics of acute myelocytic leukemia
associated with the t(8;21)(q22;q22) chromosomal
abnormality: Frequent stem cell antigen CD34.
Blood. 1992;80:470-477.
11. Haferlach T, Bennett JM, Loffler H, et al. Acute
myeloid leukemia with translocation (8;21).
Cytomorphology, dysplasia and prognostic factors
in 41 cases. Leuk Lymphoma. 1996;23:227-234.
12. Bloomfield CD, Lawrence D, Byrd JC, et al.
Frequency of prolonged remission duration after
high-dose cytarabine intensification in acute
myeloid leukemia varies by cytogenetic subtype.
Cancer Res. 1998;15:4173-4179.
13. Byrd JC, Dodge RK, Carroll A, et al. Patients
with t(8;21)(q22;q22) and acute myeloid leukemia
have superior failure-free and overall survival
when repetitive cycles of high-dose cytarabine are
administered. J Clin Oncol. 1999;17:3767-3775.
14. Grimwade D, Walker H, Harrison G, et al. The
predictive value of hierarchical cytogenetic
classification in older patients with acute myeloid
leukemia (AML): Analysis of 1,065 patients
entered into the United Kingdom Medical Research
Council AML11 Trial. Blood. 2001;98:1312-1320.
15. Baer MR, Stewart CC, Lawrence D, et al.
Expression of the neural cell adhesion molecule
CD56 is associated with short remission duration
and survival in acute myeloid leukemia with
t(8;21)(q22;q22). Blood. 1997;90:1643-1650.
16. Nguyen S, Leblanc T, Fenaux P, et al. A white
blood cell index as the main prognostic factor in
t(8;21) acute myeloid leukemia (AML): A survey
of 161 cases from the French AML Intergroup.
Blood. 2002;99:3517-3523.
17. Byrd JC, Weiss RB, Arthur DC, et al.
Extramedullary leukemia adversely affects
hematologic complete remission rate and overall
survival in patients with t(8;21)(q22;q22): Results
from Cancer and Leukemia Group B 8461. J Clin
Oncol. 1997;15:466-475.
18. Liu PP, Hajra A, Wijmenga C, et al. Molecular
pathogenesis of the chromosome 16 inversion in
the M4Eo subtype of acute myeloid leukemia.
Blood. 1995;85:2289-2302.
19. Liu P, Tarle SA, Hajra A, et al. Fusion between
transcription factor CBFβ/PEBP2β and a myosin
heavy chain in acute myeloid leukemia. Science.
1993;261:1041-1044.
20. Bitter MA, Le Beau MM, Larson RA, et al. A
morphologic and cytochemical study of acute
myelomonocytic leukemia with abnormal marrow
eosinophils associated with inv(16)(p12q22). Am J
Clin Pathol. 1984;81:733-741.
21. LeBeau MM, Larson RA, Bitter MA, et al.
Association of an inversion of chromosome 16
with abnormal marrow eosinophils in acute
myelomonocytic leukemia. N Engl J Med.
1983;309:630-636.
22. Adriaasen HJ, te Boekhorst PA, Hagemeijer AML,
et al. Acute myeloid leukemia M4 with bone
marrow eosinophilia (M4eo) and inv(16)(p13q22)
exhibits a specific immunophenotype with CD2
expression. Blood. 1993;81:3043-3051.
23. Asou N, Osato M, Okubo T, et al. Acute
myelomonocytic leukemia carrying the
PEBP2beta/MYH11 fusion gene. Leuk
Lymphoma. 1998;31:81-91.
24. Grois N, Nowotny H, Tyl E, et al. Is trisomy 22 in
acute myeloid leukemia a primary abnormality or
only a secondary change associated with inversion
16? Cancer Genet Cytogenet. 1989;43:119-129.
25. Wong KF, Kwong YL. Trisomy 22 in acute
myeloid leukemia: A marker for myeloid leukemia
with monocytic features and cytogenetically
cryptic inversion 16. Cancer Genet Cytogenet.
1999;109:131-133.
26. Langabeer SE, Grimwade D, Walker H, et al. A
study to determine whether trisomy 8, deleted 9q,
and trisomy 22 are markers of cryptic
rearrangements of PML/RARα, AML1/ETO, and
CBFB/MYH11 respectively in acute myeloid
leukaemia. Br J Haematol. 1998;101:338-340.
27. Mrozek K, Bloomfield CD. Chromosome
aberrations in de novo acute myeloid leukemia in
adults: Clinical implications. Rev Clin Exp
Hematol. 1998;5:44-67.
28. Glass JP, Van Tassel P, Keating MJ, et al. Central
nervous system complications of a newly
recognized subtype of leukemia: AMML with a
pericentric inversion of chromosome 16.
Neurology. 1987;37:639-644.
29. Holmes R, Keating MJ, Cork A, et al. A unique
pattern of central nervous system leukemia in
acute myelomonocytic leukemia associated with
inv(16)(p13q22). Blood. 1995;65:1071-1078.
30. Grimwade D, Walker H, Oliver F, et al. The
importance of diagnostic cytogenetics on outcome
in AML: Analysis of 1612 patients entered into
the MRC AML 10 trial. The Medical Research
Council Adult and Children’s Leukemia Working
Parties. Blood. 1998;92:2322-2333.
© laboratorymedicine> november 2003> number 11> volume 34
31. Groupe Francais de Cytogenetique Hematologique:
Acute myelogenous leukemia with an 8;21
translocation. A report on 148 cases from the
Groupe Francais de Cytogenetique Hematologique.
Cancer Genet Cytogenet. 1990;44:169-179.
32. Schoch C, Hasse D, Haferlach T, et al. Fifty-one
patients with acute myeloid leukemia and
translocation t(8;21)(q22;q22): An additional
deletion in 9q is an adverse prognostic factor.
Leukemia. 1996;10:1288-1295.
33. Marlton P, Keating M, Kantarjian H, et al.
Cytogenetic and clinical correlates in AML
patients with abnormalities of chromosome 16.
Leukemia. 1995;9:965-971.
Downloaded from https://academic.oup.com/labmed/article-abstract/34/11/796/2657281 by guest on 20 May 2020
34. Grignani F, Fagioli M, Alcalay M, et al. Acute
promyelocytic leukemia: From genetics to
treatment. Blood. 1994;83:10-25.
35. de The H, Lavau C, Marchio A, et al. The PML-
RAR-alpha fusion mRNA generated by the
t(15;17) translocation in acute promyelocytic
leukemia encodes a functionally altered RAR.
Cell. 1991;66:675-684.
36. Alland L, Muhle R, Hou H, et al. Role for N-CoR and
histone deacetylase in Sin 3-mediated transcriptional
repression. Nature. 1997;387:49-55.
37. Menell J, Cesarman G, Jacovina A, et al. Annexin II
and bleeding in acute promyelocytic leukemia. N Engl
J Med. 1999;340:994-1036.
38. Fenaux P, Castaigne S, Dombret H, et al. All-
transretinoic acid followed by intensive chemotherapy
gives a high complete remission rate and may prolong
remissions in newly diagnosed acute promyelocytic
leukemia: A pilot study on 26 cases. Blood.
1992;80:2176-2181.
801
 39. Tallman M, Anderson J, Schiffer C, et al. All-trans-
retinoic acid in acute promyelocytic leukemia. N Engl
J Med. 1997;337:1021-1028.
40. Fenaux P, Chastang C, Chevret S, et al. A randomized
comparison of all transretinoic acid (ATRA) followed
by chemotherapy and ATRA plus chemotherapy and
the role of maintenance therapy in newly diagnosed
acute promyelocytic leukemia. Blood. 1999;94:1192-
1200.
41. Estey E, Thall PF, Pierce S, et al. Treatment of newly
diagnosed acute promyelocytic leukemia without
cytarabine. J Clin Oncol. 1997;15:483-490.
42. Avvisati G, Lo Coco F, Diverio D, et al. AIDA (all-
trans retinoic acid + idarubicin) in newly diagnosed
acute promyelocytic leukemia: A Gruppo Italiano
Malattie Ematologiche Maligne dell’Adulto
(GIMEMA) pilot study. Blood. 1996;88:1390-1398.
43. Sanz MA, Martin G, Rayon C, et al. A modified AIDA
protocol with anthracycline-based consolidation results
in high antileukemic efficacy and reduced toxicity in
newly diagnosed PML/RAR-alpha-positive acute
promyelocytic leukemia. Blood. 1999;94:3015-3021.
44. Bernard J, Weil M, Boiron M, et al. Acute
promyelocytic leukemia: Results of treatment by
daunorubicin. Blood. 1973;41:489-496.
45. Marty M, Ganem G, Fischer J, et al. Acute
promyelocytic leukemia: Retrospective study of 119
patients treated with daunorubicin. Nouv Rev Fr
Hematol. 1984;26:371-387.
46. Avvisati G, Mandelli F, Petti MC, et al. Idarubicin (4-
demethoxydaunorubicin) as single agent for remission
induction of previously untreated acute promyelocytic
leukemia: A pilot study of the Italian cooperative
group GIMEMA. Eur J Haematol. 1990;44:257-260.
47. Avvisati G. Event-free survival (EFS) duration in
newly diagnosed acute promyelocytic leukemia (APL)
is favorably influenced by induction treatment with
idarubicin alone: Final results of the GIMEMA
randomized study (LAP389) comparing idarubicin +
ARA-C in newly diagnosed APL. Blood.
1999;94:2259a.
48. Zhang P, Wang S, Hu X. Arsenic trioxide treated 72
cases of acute promyelocytic leukemia. Chin J
Hematol. 1996;17:58-62.
49. Niu C, Yan H, Yu T, et al. Studies on treatment of acute
promyelocytic leukemia with arsenic trioxide:
Remission induction, follow-up, and molecular
monitoring in 11 newly diagnosed and 47 relapsed
acute promyelocytic leukemia patients. Blood.
1999;94:3315-3324.
50. Chen GQ, Zhu J, Shi XG, et al. In vitro studies on
cellular and molecular mechanisms of arsenic trioxide
(As2O3) in the treatment of acute promyelocytic
leukemia: As2O3 induces NB4 cell apoptosis with
down regulation of Bcl-2 expression and modulation
of PML-RAR alpha/PML proteins. Blood.
1996;88:1052-1061.
51. Chen G-Q, Shi X-G, Tang W, et al. Use of Arsenic
trioxide (As2O3) in the treatment of acute
promyelocytic leukemia (APL): I. As2O3 exerts dose-
dependent dual effects on APL cells. Blood.
1997;89:3345-3353.
802 52. Tallman MS, Nabhan C, Feusner JH, et al. Acute
promyelocytic leukemia: evolving therapeutic
strategies. Blood. 2002;99:759-767.
53. Ikeda K, Sasaki K, Tasaka T, et al. Reverse
transcription-polymerase chain reaction for PML-RAR
alpha fusion transcripts in acute promyelocytic
leukemia and its application to minimal residual
leukemia detection. Leukemia. 1993;7:544-548.
laboratorymedicine> november 2003> number 11> volume 34
54. Burnett AK, Grimwade D, Solomon E, et al.
Presenting white blood cell count and kinetics of
molecular remission predict prognosis in acute
promyelocytic leukemia treated with all-trans retinoic
acid: Result of the Randomized MRC Trial. Blood.
1999;93:4131-4143.
55. Douer D, Preston-Martin S, Chang E, et al. High
frequency of acute promyelocytic leukemia among
Latinos with acute myeloid leukemia. Blood.
1996;87:308-313.
56. Wolman SR, Gundacker H, Appelbaum FR, et al.
Impact of trisomy 8 (+8) on clinical presentation,
treatment response, and survival in acute myeloid
leukemia: A Southwest Oncology Group study. Blood.
2002;100:29-35.
57. Schoch C, Haase D, Fonatsch C, et al. The
significance of trisomy 8 in de novo acute myeloid
leukemia: The accompanying chromosome aberrations
determine the prognosis. Br J Haematol. 1997;99:605-
611.
58. Ziemin-van der Poel S, McCabe NR, Gill H, et al.
Identification of a gene, MLL, that spans the
breakpoint in 11q23 translocations associated with
human leukemias. Proc Natl Acad Sci USA.
1991;88:10735-10739.
59. Rubnitz J, Behm F, Downing J. 11q23 rearrangements
in acute leukemia. Leukemia. 1996;10:74-82.
60. Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant
proliferations. Genes Chromosomes Cancer.
1995;13:75-85.
62. Super HJ, McCabe NR, Thirman MJ, et al.
Rearrangements of the MLL gene in therapy-related
acute myeloid leukemia in patients previously treated
with agents targeting DNA-topoisomerase II. Blood.
1993;82:3705-3711.
62. Mrozek K, Heinonen K, Lawrence D, et al. Adult
patients with de novo acute myeloid leukemia and
t(9;11)(p22;q23) have a superior outcome to patients
with other translocations involving band 11q23: A
Cancer and Leukemia Group B study. Blood.
1997;90:4532-4538.
63. Caligaris MA, Strout MP, Gilliland DG. Molecular
biology of acute myeloid leukemia. Semin Oncol.
1997;24:32-4.
64. Dastugue N, Payen C, Lafage-Pochitaloff M, et al.
Prognostic significance of karyotype in de novo adult
acute myeloid leukemia. Leukemia. 1995;9:1491-1498.
65. Heinonen K, Mrozek K, Lawrence D, et al. Trisomy
11 as the sole karyotypic abnormality identifies a
group of older patients with acute myeloid leukemia
(AML) with FAB M2 or M1 and unfavorable clinical
outcome. Results of CALGB 8461. Proc Am Assoc
Cancer Res. [abstract] 1996;37:186-187.
66. Fourth International Workshop on Chromosomes in
Leukemia, 1982: Clinical significance of chromosomal
abnormalities in acute nonlymphoblastic leukemia.
Cancer Genet Cytogenet. 1984;11:332-350.
67. Bloomfield CD, de la Chapelle A. Chromosome
abnormalities in acute nonlymphocytic leukemia:
Clinical and biologic significance. Semin Oncol.
1987;14:372-383.
68. Nowell PC, Hungerford DA. A minute chromosome in
human chronic granulocytic leukemia. Science.
1960;132:1497.
69. Propp S, Lizzi FA. Philadelphia chromosome in acute
lymphocytic leukemia. Blood. 1970;36:353-360.
70. Melo JV. The diversity of BCR-ABL fusion proteins
and their relationship to leukemia phenotype. Blood.
1970;36:353.
©
71. Kurzrock R, Gutterman JU, Talpaz M. The molecular
genetics of Philadelphia chromosome-positive
leukemias. N Engl J Med. 1988;319:990-998.
72. Kantarjian HM, Talpaz M, Dhingra K, et al.
Significance of the p210 versus p190 molecular
abnormalities in adults with Philadelphia chromosome-
positive acute leukemia. Blood. 1991;78:2411-2418.
73. Kurzrock R, Shtalrid M, Gutterman JU, et al.
Molecular analysis of chromosome 22 breakpoints in
adult Philadelphia-positive acute lymphoblastic
leukemia. Br J Haematol. 1987;67:55-59.
74. Secker-Walker LM, Craig JM, Hawkins JM, et al.
Philadelphia positive acute lymphoblastic leukemia in
adults: Age distribution, BCR breakpoint and
Downloaded from https://academic.oup.com/labmed/article-abstract/34/11/796/2657281 by guest on 20 May 2020
prognostic significance. Leukemia. 1991;5:196-199.
75. Preti HA, O’Brien S, Giralt S, et al. Philadelphia-
chromosome-positive adult acute lymphocytic
leukemia: Characteristics, treatment results, and
prognosis in 41 patients. Am J Med. 1994;97:60-65.
76. Bloomfield CD, Peterson LC, Yunis JJ, et al. The
Philadelphia chromosome (Ph1) in adults presenting
with acute leukemia: A comparison of Ph1 + and Ph1-
patients. Br J Haematol. 1977;36:347-358.
77. Westbrook CA, Hooberman L, Spino C, et al. Clinical
significance of the BCR-ABL fusion gene in adult
acute lymphoblastic leukemia: A Cancer and
Leukemia Group B Study (8762). Blood.
1992;80:2983-2990.
78. Radich J, Sanders J, Buckner CD, et al. Second
allogeneic bone marrow transplants for patients
relapsing after initial transplant with TBI-containing
regimens. J Clin Oncol. 1993;11:304-313.
79. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2
study of imatinib in patients with relapsed or refractory
Philadelphia chromosome-positive acute lymphoid
leukemias. Blood. 2002;100:1965-1971.
80. Radich J, Gehly G, Lee A, et al. Detection of bcr-abl
transcripts in Philadelphia chromosome-positive acute
lymphoblastic leukemia after bone marrow
transplantation. Blood. 1997;89:2602-2609.
81. De Braekeleer M, Lin CC. 4;11 translocation-
associated acute leukemia: A comprehensive analysis.
Cancer Genet Cytogenet. 1986;21:53-66.
82. Secker-Walker LM, Prentice HG, Durrant J, et al.
Cytogenetics adds independent prognostic information
in adults with acute lymphoblastic leukaemia on MRC
trial UKALL XA. Br J Haematol. 1997;96:601-610.
83. Third International Workshop on Chromosomes in
Leukemia: Clinical significance of chromosomal
abnormalities in acute lymphoblastic leukemia. Cancer
Genet Cytogenet. 1981; 4:111.
84. Bloomfield CD, Secker-Walker LM, Goldman AI, et
al. Six-year follow-up of the clinical significance of
karyotype in acute lymphoblastic leukemia. Cancer
Genet Cytogenet. 1989; 40:171-185.
85. Janssen JWG, Ludwig W-D, Borkardt A, et al. Pre-
pre-B acute lymphoblastic leukemia: High frequency
of alternatively spliced ALL1-AF4 transcripts and
absence of minimal residual disease during complete
remission. Blood. 1993;82:3705-3711.
86. Slovak ML, Kopecky KJ, Cassileth PA, et al.
Karyotypic analysis predicts outcome of pre- and
postremission therapy in adult acute myeloid
leukemia (AML): A SWOG/ECOG intergroup study.
[Suppl 1, abstract 2795] Blood. 1998;92:678a.
87. Uzunel M, Mattsson J, Jaksch M, et al. The
significance of graft-versus-host disease and
pretransplantation minimal residual disease status
to outcome after allogeneic stem cell
transplantation in patients with acute lymphoblastic
leukemia. Blood. 2001;98:1982-1985.