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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4662-4667
MLL and CALM Are Fused to AF10 in
Morphologically Distinct Subsets of Acute Leukemia With
Translocation t(10;11): Both Rearrangements Are Associated With a
Poor Prognosis
By
M.H. Dreyling,
K. Schrader,
C. Fonatsch,
B. Schlegelberger,
D. Haase,
C. Schoch,
W.-D. Ludwig,
H. Löffler,
T. Büchner,
B. Wörmann,
W. Hiddemann, and
S.K. Bohlander
From the Department of Hematology/Oncology, University of
Göttingen, Göttingen, Germany; the Institute of Medical
Biology, University of Vienna, Vienna, Austria; the Institute of Human
Genetics, University of Kiel, Kiel, Germany; the
Robert-Rössle-Clinic, Department of Hematology/Oncology and Tumor
Immunology, Humboldt-University of Berlin, Berlin, Germany; the
Department of Medicine, University Hospital of Kiel, Kiel,
Germany; the Department of Hematology/Oncology, University of
Münster, Münster, Germany; and the Institute of Human
Genetics, University of Göttingen, Göttingen, Germany.
 |
ABSTRACT |
The translocation t(10;11)(p13;q14) has been observed in acute
lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). A
recent study showed a MLL/AF10 fusion in all cases of AML with
t(10;11) and various breakpoints on chromosome 11 ranging from q13 to
q23. We recently cloned CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene), the fusion partner of AF10 at 11q14 in the monocytic cell line U937. To further define the role of these genes
in acute leukemias, 10 cases (9 AML and 1 ALL) with cytogenetically proven t(10;11)(p12-14;q13-21) and well-characterized morphology, immunophenotype, and clinical course were analyzed. Interphase fluorescence in situ hybridization (FISH) was performed with 2 YACs
flanking the CALM region, a YAC contig of the MLL
region, and a YAC spanning the AF10 breakpoint. Rearrangement
of at least one of these genes was detected in all cases with balanced
t(10;11). In 4 cases, including 3 AML with immature morphology (1 AML-M0 and 2 AML-M1) and 1 ALL, the signals of the CALM YACS
were separated in interphase cells, indicating a translocation
breakpoint within the CALM region. MLL was rearranged
in 3 AML with myelomonocytic differentiation (2 AML-M2 and 1 AML-M5),
including 1 secondary AML. In all 3 cases, a characteristic
immunophenotype was identified (CD4+,
CD13 , CD33+, CD65s+).
AF-10 was involved in 5 of 6 evaluable cases, including 1 case without detectable CALM or MLL rearrangement. In 2 complex translocations, none of the three genes was rearranged. All
cases had a remarkably poor prognosis, with a mean survival of 9.6 ± 6.6 months. For the 7 AML cases that were uniformly treated according
to the AMLCG86/92 protocols, disease-free and overall survival was
significantly worse than for the overall study group (P = .03 and P = .01, respectively). We conclude that the
t(10;11)(p13;q14) indicates CALM and MLL rearrangements
in morphologically distinct subsets of acute leukemia and may be
associated with a poor prognosis.
| |
INTRODUCTION |
MALIGNANT TRANSFORMATION is a multistep
process that involves the sequential alteration of genes regulating
cell growth and/or differentiation. Many of the genes involved
in leukemogenesis have been identified by the molecular analysis of
nonrandom chromosome abnormalities.1
The rare, but recurring translocation t(10;11)(p13;q14) has been
observed in acute lymphoblastic leukemia (ALL) as well as acute myeloid
leukemia (AML).2-5 A recent study showed a MLL/AF10 fusion in all cases of AML with t(10;11) and various
breakpoints on chromosome 11q, including 6 cases with rearrangement of
chromosomal band 11q13.6 MLL (also called
ALL1, Htrx1, and HRX) is involved in
translocations with up to 40 different translocation partner genes in
AML as well as acute lymphoid leukemia, including the t(10;11)(p13;q23)
in AML.7-12 In this translocation, the fusion partner genes
AF-10 and MLL are often found to be involved in complex
rearrangements (inversions/insertions), because they are transcribed in
opposite direction relative to the telomere/centromere orientation.6 These complex rearrangements may be
interpreted as t(10;11) (p13;q14-21).
The molecular characterization of the t(10;11)(p13;q14) in the
monocytic cell line U937 identified a different breakpoint on
chromosome 11, involving the previously unknown gene
CALM.13,14 CALM has a very high homology to
the murine clathrin assembly protein ap-3.15
Interestingly, both translocations t(10;11) have the same fusion
partner gene on chromosome 10, the putative transcription factor
AF10.11,14,16
To further define the involvement of the three genes AF10,
CALM, and MLL in acute leukemias, we analyzed 10 cases
(9 AML and 1 ALL) with cytogenetically proven t(10;11)(p12-14;q13-21)
and well-characterized morphology, immunophenotype, and clinical
course. Only cytogenetic material stored in fixative for several years was available, which was not suitable for an analysis at the RNA level.
An interphase fluorescence in situ hybridization (FISH) approach was
chosen.17 Nonchimeric YACs from the genomic region of the
three genes were used. A translocation was assumed when one of the YAC
signals was split resulting in three hybridization signals in a diploid
interphase nucleus.
| |
MATERIALS AND METHODS |
Patient samples.
This study was designed and performed according to the updated
declaration of Helsinki. Patient material was collected from 725 cases
that entered the studies of the German AML Cooperative Group 86 and 92 and that were subjected to cytogenetic analysis.18 Based on
the cytogenetic data and the availability of material, 8 cases with
t(10;11)(p12-14;q13-21) were identified
(Table 1). In addition, 1 adult ALL (no.
10) and 1 infant AML (no. 6) with t(10;11) were included in this
series. All cases were morphologically classified according to the
French-American-British (FAB) criteria and were reviewed by an
independent reference hematologist (H.L.).19 Immunophenotyping was performed according to the consensus protocol for
flow cytometric immunophenotyping of hematopoietic
malignancies.20,21 Clinical data were obtained from the
AMLCG study center or directly from the patients' physicians (patients
no. 6 and 10). Patients no. 3 and 7 had been previously treated for
malignant T-cell lymphoma and were in complete remission. All AML
patients received a uniform chemotherapy according to the AMLCG86/92
protocols comprising double induction, followed by intensive
consolidation and 3 years of monthly maintenance therapy.18
Patient no. 6 (pediatric patient) and patient no. 8 (initially
misclassified as ALL) were treated differently (Table 1).
Mononuclear cells of patient samples were grown in short-term culture
or processed directly, harvested using standard cytogenetic techniques,
and stored in Carnoy's solution until final analysis, as previously
published.22
FISH probes.
YAC-derived FISH probes were generated either by a sequence-independent
amplification technique or nick translation (MLL
YACs).23,24
For AF10, a YAC (807b3, 1,050 kb) from the Centre d'Etude
Polymorphisme Humain (CEPH) library had been previously identified that
spans the breakpoint region on 10p and reliably detects the breakpoint
in U937.14
For MLL, we used a pool of two YACs (785c6 and 856b9) that span
the MLL gene and approximately 1.0 mega-bp of distally flanking sequences, because 11q23 translocations are often associated with interstitial deletions.17,25,26
For CALM, the Mega-YAC Library from CEPH was screened with the
previously reported CALM primers NG.T45 and NG.B362.14 In addition, 5 flanking YACs of the region were identified using the
Whitehead web pages (www.genome.wi.mit.edu).27,28 A total of 9 YACs were evaluated by FISH for chimerism (hybridization with
normal peripheral blood cells) and were mapped relative to the
CALM breakpoint (hybridization with U937). Based on the
intensity of hybridization signal, 2 YACs (proximal 785c1, 1,390 kb,
and distal 914D9, 1,190 kb) were chosen for interphase analysis.
Hybridization.
Dual-color FISH was performed with the two YAC-derived probes of the
CALM region as well as the AF10 YAC or the MLL
probe and the corresponding centromeric probe (CEP10 and CEP11 Spectrum Orange; Vysis, Downers Grove, IL) to exclude numerical chromosomal aberrations (Fig 1).
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| Fig 1.
(A through C) Interphase FISH of patient no. 1 (AML with
AF10 and CALM rearrangement, Table 1). Three AF10
signals (green), indicating a split of one YAC signal, and two
centromere 10 signals (red) are detectable in (A). In (B), the proximal
(green) and the distal CALM YAC (red) are separated, indicating
a breakpoint within this genomic region. Two MLL signals
(green) and two centromere 11 signals (red) suggest no rearrangement of
the MLL region in (C). (D through F) Interphase FISH of patient
no. 8 (AML with AF10 and MLL rearrangement). Three
AF-10 signals (green), indicating a split of one YAC signal, and two
centromere 10 signals (red) are detectable in (D). In (E), the proximal
(green) and the distal CALM YAC (red) are colocalized,
excluding a rearrangement of this genomic region. In (F), the detection
of three MLL signals (green), but only two centromere 11 signals (red) indicate a split of one MLL probe (C).
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FISH was performed as previously described.29 Briefly, the
hybridization solution contained approximately 0.1 µg of each probe,
1 µg human Cot1-DNA, 0.6 µg human placental DNA, and 1 µg salmon
sperm DNA/slide in a 10 µL volume. The probes were either directly
labeled with Cy-3-dUTP (Vysis) or biotinylated and detected with
fluorescein isothiocyanate (FITC)-conjugated avidin and amplified with
antiavidin-FITC (16-Bio-dUTP [Boehringer Mannheim, Germany]; FITC-avidin and FITC anti-avidin [Vector, Burlingame, CA]). The slides were counterstained with
4 ,6-diamidino-2-phenylindole dihydrochloride (DAPI) and
were analyzed using a fluorescence microscope (Zeiss, Jena, Germany).
For each case, at least 100 single, intact interphase cells were
analyzed.
For Fig 1, separate gray scale images of DAPI-stained cells and
fluorescence signals were captured using a charge-coupled device camera
(Xillix, Richmond, British Columbia, Canada) and were pseudocolored and
merged using Adobe Photoshop software (Adobe Systems, Mountain View,
CA).
Statistical analysis.
Survival data were analyzed using the  2 test using PC
Statistik software (Topsoft, Hannover, Germany).
| |
RESULTS |
Patients' characteristics.
Our study group included 1 adult T-ALL (no. 10, Table 1), 1 infant AML
(no. 6), and 8 adult AML. The morphology of the myeloid leukemias were
classified as immature (FAB M0) in 1 case (no. 8) and as leukemia with
minimal maturation (FAB M1) in 3 cases (no. 5, 7, and 9). Significant
maturation at or beyond the promyelocyte stage (FAB M2) was diagnosed
in 2 cases (no. 2 and 3) and monocytic differentiation (FAB M5) in 3 cases (no. 1, 4, and 6).
Leukocyte counts at presentation were high, but varied significantly
within the study group (mean, 23,900/µL; range, 200 to 60,800/µL).
All patients with t(10;11) were rather young (36.7 ± 19.9 years
old). There was no gender bias (5 male and 5 female).
FISH/cytogenetics.
Rearrangements of AF10 and/or either CALM or
MLL were detected in all cases with balanced t(10;11).
MLL rearrangements were detected in 3 of 8 cases (no. 1, 2, and
3; Table 1), including the only cytogenetically identified inversion
11.
CALM was rearranged in another 4 patients (no. 7 through 10)
with balanced translocation t(10;11).
All 5 cases of 7 with MLL or CALM rearrangements, which
were evaluable, had a rearrangement of AF10. In addition, in 1 case (no. 6) with a balanced translocation t(10;11), the AF10
probe was split, indicating a breakpoint within this region, but no MLL or CALM rearrangements were detected.
No rearrangements were detected in the 2 patients with complex
rearrangements (no. 4 and 5). However, for case no. 4, cell material
was only sufficient for hybridization with the CALM
probes.
Morphology and immunophenotype.
All cases with MLL rearrangement showed a myeloid maturation at
or beyond the promyelocyte stage or a monocytic morphology according to
the FAB classification (M2 or M5), including 1 secondary AML after
treatment for high malignant T-cell lymphoma.19
In contrast, cases with CALM rearrangement showed a rather
immature phenotype (M0 or M1). In fact, case no. 8 was initially misdiagnosed as ALL and treated accordingly.
A CALM rearrangement was detected in the only ALL in this
series. The morphological diagnosis was confirmed by the typical immunophenotype with expression of various T-cell antigens and coexpression of CD10, but absence of a myeloid marker (CD11c) or B-cell
antigens.
A complete immunophenotype was available in only 1 of 3 AML with
CALM rearrangement (no. 7). In agreement with the
undifferentiated morphology of this case, leukemic blasts expressed
antigens often associated with immature morphologic subtypes (ie, CD7
and CD34). Of the panmyeloid antigens tested, only CD13 was weakly
expressed. Additionally, however, strong positivity of myeloperoxidase
was found.
All 3 cases with MLL rearrangement were positive for the
panmyeloid antigens CD33 and CD65s but lacked CD13 and CD15 and
coexpressed CD4. Expression of markers associated with immaturity
varied. In addition, 1 case (no. 1) showed coexpression of CD7 and
CD10.
Clinical course.
In agreement with previous reports, hyperleukocytosis was detected in
all cases with MLL rearrangements (mean, 35,000/µL; range,
13,800 to 60,800/µL).30-33 Leukocyte counts were also
high in cases with CALM rearrangements (mean, 27,400/µL;
range, 1,300 to 60,800/µL). However, the number of cases is too small
for statistical evaluation.
The overall survival of the total group was remarkably poor (9.6 ± 6.6 months), although, initially, 5 of 8 evaluable patients reached a
complete remission. There was no significant difference between
patients with MLL or CALM rearrangements. For the 7 patients who were treated according to the AMLCG86/92 protocol,
disease-free survival and overall survival were 5 ± 4.9 months and
11 ± 7.2 months, respectively. The survival data of these patients
were significantly worse than for the overall study group. After 14 months, none of the t(10;11) patients but 40% of the overall group were still disease-free (P = .03, 2), and after
19 months, none of the t(10;11) patients but 49% of the overall group
were still alive (P = .01, 2;
Fig 2).18
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| Fig 2.
Overall survival in AML with t(10;11). Kaplan-Meier plots
of the overall survival of patients with AML with t(10;11)(p13;q14) (n
= 7; solid line) and the total study group with identical treatment (n = 725; dotted line).18
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| |
DISCUSSION |
The translocation t(10;11)(p13;q14) is a recurring chromosomal
abnormality that has been observed in acute lymphoblastic as well as
AML.2-5 On the molecular level, two types of
t(10;11)(p12-p14;q13-q21) have been characterized so far. One type
results in a MLL/AF10 fusion, the other causes a
CALM/AF10 fusion.11,14 We performed this study to
define the relevance of MLL and CALM rearrangements in
acute leukemia with t(10;11)(p13;q13-21). Both types of rearrangements were detected with similar frequency in cases with balanced
translocation t(10;11). CALM was rearranged in AML as well as
in ALL. Interestingly, the AML cases with CALM rearrangement
had a rather immature morphology, and 1 case was initially misdiagnosed
as ALL. This may have been also the case for some of the initially
reported ALL cases with t(10;11) when immunophenotyping was not yet
routinely performed.3 However, our series included a
well-characterized lymphoblastic leukemia as well as myeloid leukemias,
suggesting that CALM may play a critical role in the early
progenitor/stem cell before either myeloid or lymphoid differentiation
takes place. CALM has a very high homology to ap-3, a
murine clathrin assembly protein.15 So far, CALM is
the only protein interacting with clathrin that has been found to be
involved in malignant transformation. A transactivation domain that was
recently identified in CALM could be critical for the
transformation potential of CALM/AF10.34 However,
further studies are necessary to define the precise mechanism by which the CALM/AF10 fusion contributes to malignant transformation.
In contrast to the rather undifferentiated morphology of myeloid
leukemias with CALM rearrangement, cases with MLL
rearrangement showed a monocytic morphology or a myeloid maturation
beyond the promyelocyte stage. Accordingly, all previously reported
leukemias with t(10;11) and rearrangement of MLL either
detected by FISH or by other molecular techniques, were AML-M4 or
M5/M5a.6,35,36 Similarly, MLL rearrangements in
general are strongly correlated with monocytic or myelomonocytic
phenotypes.30,36 In contrast, Poirel et al37
detected MLL rearrangements in 20% of AML-M1. However, these
translocations did not involve chromosome 10. In fact, although
MLL rearrangements are detected in AML as well as ALL,
different translocation partner genes are usually
involved.36 For example, t(4;11) and t(11;19)(q23;p13.3)
are detected in ALL, whereas t(6;11), t(9;11), and t(11;19)(q23;p13.1)
are common translocations in various subtypes of AML.36
Therefore, the results of Poirel et al37 that included
t(6;11),t(9;11), and an uncharacterized t(11;19) might not be
applicable to leukemias with t(10;11).
In accordance with a previously published series of AML with
MLL rearrangements, in our series, all 3 cases with MLL
rearrangement were CD4+, CD13,
CD33+, CD65s+.20 The latter three
markers are panmyeloid markers that are rather broadly
expressed.21 Therefore, this immunophenotype does not
represent an aberrant expression of different lineage- or
maturity-specific markers as detected in the majority of
leukemias.38 Hence, we do not consider this immunophenotype
as leukemia-specific for MLL translocation, although the only
completely characterized AML with CALM rearrangement had a
clearly distinct immunophenotype (CD4,
CD13+, CD33, CD65s).
AF10 is the first fusion partner of MLL, which is fused
to another gene in a different translocation, emphasizing its important role in malignant transformation. It is thought that AF10
functions as a transcription factor and that the zinc finger might
constitute a DNA binding domain.12,16 Interestingly, 1 case
with a balanced translocation t(10;11) (no. 6) showed a breakpoint
within the AF10 region, but did not have a CALM or
MLL rearrangement. Translocations of 11q23 are often associated
with distal interstitial deletions that would make it difficult to
detect the translocation by FISH. However, our MLL probe, which
encompasses approximately 1 mega-bp of 3 flanking sequences, was
able to detect these kinds of translocations in previous
studies.17,35 Alternatively, another partner gene on
chromosome 11 may be involved.
So far, MLL rearrangements have been shown to be a negative
prognostic factor, especially in childhood ALL.31-33 For
AML, data are sparse and contradictory. In a series of pediatric AML,
patients with t(9;11)(p22;q23) had a better outcome, whereas Lo Coco et al39 identified MLL rearrangements as a negative
prognostic factor in ALL and AML.39,40 In infant AML,
11q23/MLL abnormalities had no effect on
survival.31
In our study, all cases with t(10;11) had a remarkably poor prognosis.
This holds up for the subpopulation of 7 AMLCG86/92 patients whose
event-free and overall survival was significantly worse than the
survival data of the overall study group.18 Therefore, our
results suggest that cytogenetic/molecular analysis may be used to
identify this subgroup with poor prognosis.
In summary, we were able to identify a MLL or a CALM
rearrangement, each in approximately half of the leukemias with a
t(10;11)(p13,q13-21). Moreover, MLL or CALM
rearrangements were found in leukemias with different morphology.
MLL translocations were identified in leukemias with monocytic
morphology or maturation beyond the promyeloid stage, whereas
CALM rearrangements were detectable in immature leukemias as
well as ALL. Further studies are necessary to characterize the
biological characteristics of these molecular alterations.
Recently, Kobayashi et al41 reported 4 cases of acute
leukemia with CALM rearrangements that were studied by FISH.
However, the cases were not classified according to the FAB criteria.
| |
FOOTNOTES |
Submitted November 17, 1997;
accepted February 3, 1998.
Address reprint requests to M.H. Dreyling, MD, Department of
Hematology/Oncology, University of Göttingen, Robert Koch-Street 40, D-37075 Göttingen, Germany.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank H. Döhner for generously providing the MLL YACs
and C. Sauerland for assistance in statistical analysis.
| |
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Abstract
Introduction
Abstract