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ALL-I Gene Rearrangements in DNA Topoisomerase I1 Inhibitor-Related
Leukemia in Children
By Carolyn A. Felix, Matthew R. Hosler, Naomi J. Winick, Margaret Masterson, Albert E. Wilson,
and Beverly J. Lange
We examinedclinical,morphologic,andcytogeneticfeawithin the ALL-l gene were similar to sporadic cases. The
tures and ALL-1 (MLL, Html, H M I gene rearrangements in
resub of this analysis suggest the following: (1)In most
17 cases of secondary leukemia that occurred 11 months to
pediatric cases of topoisomeraseII inhibitor-associated leu9 years from diagnoses of primary cancers in children who
kemia, there is disruption of the breakpoint cluster region
received topoisomeraseII inhibitors or developed secondary of the ALL-l gene at chromosomal band llq23.(2) Exposure
leukemias typicalof those associatedwith this therapy. Prihistories varyin secondary 1 lq23 leukemia, asthe only topomary diagnoses included nine solid tumors and
eight leukeisomerase II inhibitor was dactinomycinin one case, and,in
mias. Ten secondary leukemias were acute myeloid leukeII inhibitor was adminisanothercase,notopoisomerase
two wereacute
mia(AML),onewas
ofmixedlineage,
tered. (3)There is clinical,morphologic,cytogenetic,and
lymphoblastic leukemia (ALL), and four presented as myelo-molecular heterogeneityin pediatric secondary llq23 leukedysplasia. Of 15 cases with llq23 involvement, 11 (73%)
mia. (4) Therearesomesurvivorsofpediatricsecondary
were cytogenetically identifiable; four cases had molecular
1lq23 leukemia, but the outcome is most often fatal.
By Southernblot,rearrangements
rearrangementonly.
0 1995 by The American Society of Hematology.
T
HE EPIPODOPHYLLOTOXIN anticancer drugs etoposide and teniposide are nonintercalating inhibitors of
the nuclear enzyme DNA topoisomerase
The anthracyclines and dactinomycin are intercalating inhibitors that form
a complex with DNA and topoisomerase IL7.' In addition to
causing chromosomal deletions andDNA recombinations
that are cytotoxic to cancer cells, topoisomerase I1 inhibitor
chemotherapy in humans has been implicated in leukemogenic trans location^.^
Translocations of chromosome band llq23, most commonly with band 9p21, are present in half the cases of secondary leukemia associated with DNA topoisomerase I1 inhibitor~.~
Variant reciprocal partners of llq23 include
chromosomes 1, 2, 3, 16, 17, and 19.1°-'* The t(8;21) is
present as a recurring chromosomal abnormality in several
other cases.I3-l5Cases of t(l5; 17) acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML) with inv(l6)
related to DNA topoisomerase I1 interactive drugs have also
been de~cribed.'~"'
Chromosome band 1lq23 is involved in reciprocal translocations in mostsporadicacutelymphoblastic
leukemias
(ALLs) and AMLs of idants and young children. The same
From the Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School
of Medicine, Philadelphia, PA; the Center for Cancer and Blood
Disorders, Children's Medical Center of Dallas, University of Texas
Southwestern Medical Center, Dallas, T X ; andthe Department of
Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
Submitted August 19, 1994; accepted January 11, 1995.
C.A.F. is the recipient of a Leukemia Society of American Special
Fellow Award.
Address reprint requests to Carolyn A. Felix, MD, Division of
Oncology, Department of Pediatrics, Room 9093, Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia,
PA 19104.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8511-0021$3.00/0
3250
breakpointclusterregionwithin
the ALL1 (MLL, Htrxl,
HRX) oncogene at band 1lq23 for sporadic cases is disrupted
in most reported cases of epipodophyllotoxin-related llq23
leukemia. 12.18-26However, in one case of W a t r i c etoposiderelated AML with at( 1l ; 19)(q23;p13), we reported an lq23
1
translocation
breakpoint
outside the ALL-I genomic
breakpoint cluster.I8 Although a limited number of children
have been examined, most molecular analyses
of 1 1q23 chromosomalbreakpointsinsecondaryAMLhaveinvolved
ad~lts.'*.'~**~
The present study explores the molecular diversity and provides further clinical definition to DNA topoisomerase 11 inhibitor-related leukemia in a pediatric population.
MATERIALS AND METHODS
Leukemic specimens from children previously treated for a primary cancer and diagnosed with secondary leukemia were obtained
from the Children's Hospital of Philadelphia (Philadelphia, PA),
Dallas (Dallas, TX) and Cook-Fort Worth (Forth Worth, TX) Children's Hospitals, Children's Hospital of Cincinnati (Cincinnati, OH),
Memorial Sloan Kettering Cancer Center (New York, NY), University of Connecticut Health Center (Farmington), Kaiser Permanente
(Los Angeles, CA), and Indiana Oncology-Hematology Consultants
(Indianapolis). Molecular studies were approved by the Institutional
Review Board at the Children's Hospital of Philadelphia, and individual institutions had provisions either through consent for reference laboratory specimens or for the use of extra diagnostic materials
for research. The diagnoses of secondary leukemia were made by
morphologic and immunohistochemical examination of the marrow
and by fluorescence-activated cell sorter analysis with standard
monoclonal antibodies." Cytogenetic analyses were performed by
individual Childrens Cancer Group- or Pediatric Oncology Groupapproved laboratories. Molecular analyses also were performed on
the cell line B1, which wasderived from t(4; 1 l)(q21;q23) secondary
ALL cells.''
Leukemic marrow cells were examined by Southern blot analysis
using standard methodology. Genomic DNA wasisolated from cryopreserved or fresh marrow mononuclear cells using 4 m o m guaniFirst,
dine isothiocyanate-5.7 mom CsCl gradients as
BamHI- and, in some cases, HindIII-digested genomic DNAs were
analyzed with the B859 probe, an 859-bp BamHI fragment of ALLI cDNA that spans exons 5 through 1 1 , the region of the ALLI genomic breakpoint c1uster.'2.'8,22To potentially identify 1lq23
breakpoints not located within the ALL-l genomic breakpint cluster,
select cases were assessed for involvement of a more 5' site in ALLI . The 5' region of ALL-I was studied in HindIII- or Bgl 11-digested
Blood, Vol 85, No 11 (June l ) , 1995: pp 3250-3256
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THERAPY-RELATEDLEUKEMIA
3251
h
B
m
n
m
(v
U
W
h
m
c
.3 kb
26 kb -
8 kb-
8859/Bam HI
C Cen
Tel
+
2
+
3 4
9-135-8
1
14-17 18
19
20 21
20 kb
I
Fig 1. (A) Genomic Southern blot of BamHI-digested DNA hybridized with B859 human ALL-7 cDNA probe spanning exons 5 through 11,
the region of the breakpointcluster.= Several cases of secondary llq23 leukemia with one or two rearrangements of the ALL-7 gene within
the breakpointcluster as well as unrearranged cases are shown. Sporadic ALL cell line R S 4 l l is positive control.Human placental DNA and
human peripheral blood lymphocyte(PEL) DNA show the germline pattern. Numbers
above the lanes correspond t o patient IPt) numbers in
Tables 1 and 2, and karyotypes are indicated. (B) Germline pattern of the region of the ALL-I gene 5' t o the breakpoint cluster in karyotypepositive leukemic marrow DNA. (C) Schematic of the genomic regions recognized by ALL-I cDNA probe B859 and the 5' cDNA probe, SKV3.=
DNAs using as probe a 3.8-kb EcoRl fragment of ALL-I cDNA.
SKV3, spanning exons 1 through 5 andlocatedimmediately 5' of
the breakpoint cluster (Fig l)."
The clinical featuresandkaryotypes in cases I. 3 , 6, IO, 13, 15,
and 17, andmolecular analyses of the ALL-l genomic breakpoint
cluster region in cases 1 and 15 have been described (Tables I and
I.IX.~X.ZI
RESULTS
Clinical,demographic, and morphologic features. Demographic features, primary diagnoses, treatment regimens,
French-American-British (FAB) morphologies
and
outcomes are summarized in Table 1. Each child had received
a DNA topoisomerase I1 inhibitor or developed secondary
leukemia typical of that associated with this therapy. Patients
represented a diverse population of children and both sexes.
Overrepresentation of any one ethnic background was not
apparent.Therewerenine
malesandeight
females aged
from 5 to 14.7 yearsat onset ofthesecondaryleukemia.
Intervals between diagnoses of primary cancer and secondary leukemiarangedfrom
1 I months to 9 years. Primary
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FELIX
3252
AL
Table 1. Demographic and Clinical Features of Pediatric Secondary Leukemias
P R I M A R YC A N C E R
Therapy
S E C O N D A R YL E U K E M I A
I
Mos
from J
Therapy
Some clinical features in cases 1. 3,6, IO, 13, 15, and 17 have been described. Case 1 in the present study was case 8 in Winick et al.” Cases
3 and 6 were cases 13 and 16, respectively, in Rubin et al.”Cases 13 and 17
1 and 15 were cases 1 and 2, respectively, in Felix etCases
were cases 4 and 6, respectively, in Heyn et al.31 Theclinical history in case 10 was reported in a case report.” Cytoreduction for BMT in case
6 was with melphalan and total body irradiation.
Abbreviations: Pt, patient; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MLL, mixed lineage leukemia; MDS, myelodysplastic syndrome; DX, diagnosis; OS, osteosarcoma; HD. Hodgkin‘s disease; NBL, neuroblastoma; PNET, peripheral neuroectodermal tumor;
NHL, non-Hodgkin‘s lymphoma; RMS, rhabdomyosarcoma; W, white; B, black; H, Hispanic; A-ase, L-asparaginase; ADR, Adriamycin (doxorubicin); AMD, dactinomycin; Ara-C, cytosine arabinoside; BCNU, carmustine; BMT*, bone marrow transplant; CBDCA, carboplatin; Cort**, corticosteroids {dexamethasone, prednisone, methylprednisolone, or intrathecal hydrocortisone); CPPD, cisplatin; CPM, cyclophosphamide: DNM, daunorubicin; EPO, erythropoietin; 5-AZA, 5-azacytidine;HU, hydroxyurea; IFOS, ifosfamide; MIT, mitoxantrone; MTX, methotrexate; PCZ, procarbazine;
6MP, 6-mercaptopurine; 6TG, 6-thioguanine; VCR, vincristine; VLB, vinblastine; VM26, teniposide; VP16, etoposide; XRT, radiation therapy; FAB,
French-American-British; DOD, dead of disease; DOC, dead of complications; NED, no evidence of disease.
Cytoreduction regimen not listed.
diagnoses included nine solid tumors and eight leukemias.
Ninesecondaryleukemiasweremonoblasticvariants
of
AML or mixed lineage leukemia (MLL), one was FAB M1
AML, one was FAB M2, four presented as myelodysplasia
(MDS), and two were ALL. In 13 cases, there was previous
DNA topoisomerase I1 inhibitor exposure to epipodophyllotoxin in combination with an anthracycline. In two
cases,
prior treatment was with an anthracycline without epipodophyllotoxin. The only previous DNA topoisomerase I1 inhibitor in one case was dactinomycin and, in another case, no
DNA topoisomerase I1 inhibitor was administered.
Karyotypic abnormalities in secondary leukemias. Complete karyotypes of the 17 secondary leukemias are listed in
Table 2. Elevencases had translocationof chromosome band
1 lq23 with bands lp32,3q25,4~21,9~21-22,
or 19p13. One
case showed del(1 l)(q23). In five othercases, the karyotypes
were normal or suggested unrelated structural abnormalities
or only a numerical abnormality. In one case with multiple
cytogenetic abnormalities not involving chromosome band
l lq23, there were monosomies of chromosomes 5 and 7,
more typical of the alkylator-induced myelodysplasias and
leukemias (Table 2).3’.32
Localization of genomic breakpoints in secondary I Iq23
leukemia by Southern blot analysis. Results of Southern blot
analysis of 17cases of pediatricsecondaryleukemiasare
shown inTable 2. Grouped according to whether cytogenetics
showed an 1 lq23 translocation and whether there was ALLI gene rearrangement on Southernblotanalysis,cases
1
through 10 were karyotype +/molecular +; cases 1l through
14, karyotype -/molecular + ; case 15, karyotype +/molecular
-; and cases 16 and 17, karyotype -/molecular
-.
In 8 of 15 cases with cytogenetic and/or molecular rearrangement of chromosomeband llq23, Southem blot
analysis of BamHI-digested genomic DNA with the B859
probe showed the normal allele and two additional bands
consistent with both derivative chromosomes that resulted
from the translocation (Fig l). In six cases, only one derivativechromosomewas
detected by theprobe. In a previouslyreported case of etoposide-related AML with a
t(l1; 19)(q23;p13), the llq23 translocation breakpoint was
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THERAPY-RELATED
LEUKEMIA
Table 2. Karyotypes and ALL-I Gene Status in Pediatric Secondary Leukemias
Case
1
2
11
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
ALL-l 8859
Karyotype
46,XY,t(9;11)(p22;q23) 115 cellsl
46,XX,t(11;19)(q23;p13.3) 110 cellsl/46,XX 110 cellsl
47,XX,+8,t(11;19)(q23;p13) 119 cells1/48,XX,+8,+8,t(ll;19)(q23;p13) 16 cellsl
46,XX,t(9; )(p22;q23) 127 cellsl
46,XY,t(llq-;19p+) 125 cellsl
46,XY,t(l;7)(q32;q32-34),inv(2)(p2l;q37),t~3;ll)(q25;q23~,t~7;?~~q22;?~
129 cellsl
46,XX,t(l; 1l)(p32;q23) 121 cellsll46,XX 114 cellsl
47,XX,+de1(6)(7q27)/47,XX,+8,de1(6)(q27),del(l l)(q23) 130 cellsl
. 46,XY,t(9;11)(p22;q23) 120 cellsl
46,XY.t(4;ll)(qZl;q23) [7 cellsl/46,XY 118 cellsl
47,XX,add(l)(p32),+mar 12 cellsl/46,XX 138 cellsl
46,XX,del(ll)(ql4),add(14)(p?11.2)
cellsl116 cellsl/46,XX [4
cellsl
46,XX,t(l1;20)(p15;q11.23) 115 cellsl/46XX 15 cellsl
111 46,XY
cells1/46,XY,+8,-10,t~l1;19)(q23;p13.3),del~17)(pll.2~,+nonclonal abnormalities 17 cells]/
46,XY,-l,+der(l~t~l;?)(p2l;?~,+8,-lO,t~l1;19~~q23;p13.3~,del~17~~pll.2~,+nonclonal
abnormalities 12 cellsl
85-94(4n),XXW 119 cellsl/n=66 11 cell1
R2
R2
R2
R1
R1
R2
R1
R2
R2
R2
RI
R2
RI
RI
G
G
45,XY,hsr~2~~q22),-5,der(7)de1~7~~qll.23~hsr~7)(ql1.23~,der~12~t~12;19~~pll.2;ql2~,der~17~t~5;l7~~pl2;pll.2~,-l9,+marl
G
119 cellsl/related nonclonal 11 cellY46,XY 12 cellsl
The status of the All-7 gene in the breakpoint cluster region and partial karyotypes in cases 1 and 15 were reported previously;" additional
molecular analyses of the ALL-7 genomic breakpoint cluster region and the 5' region of ALL-7 in case 15 were performed herein. Case 1 in the
present study was case 8 in Winick et al." Cases 1 and 15 were cases 1 and 2, respectively, in Felix et aL1* Cases 3 and 6 were cases 13 and
16, respectively, in Rubin et al.'" Cases 13 and 17 were cases 4 and 6, respectively, in Heyn et al.31Molecular analyses on case 10were performed
on the cell line B1 derived from the secondary leukemia in a previous case report?'
Abbreviations: R I , one rearrangement; R2, two rearrangements; G, germline.
not located within the ALL-l genomic breakpoint cluster
(case 15)." In the present study, this leukemia was further
analyzed by hybridization of HindIII-digested DNAwith
the B859 fragment of ALL-l cDNA, confirming thatthe
translocation breakpoint was not within the region of the
breakpoint cluster. Involvement of the 5' region of ALL-l
also was excluded.
Of l 1 cases with cytogenetically detectable abnormalities
of chromosome band 1lq23, 10 had rearrangements within
the ALL-l genomic breakpoint cluster. Included was a case
of secondary t( 1 1;19) MLL, where the previous Hodgkin's
disease therapy included alkylating agents and irradiation,
but not a DNA topoisomerase I1 inhibitor (case 5 , Tables l
and 2).
Four cases of secondary 1lq23 leukemia with molecular
ALL-l gene rearrangements within the breakpoint cluster
did not show llq23 abnormalities by karyotype (Table 2).
Included was a case of secondary MDS examined after evolution to secondary AML (case 14). This leukemia showed
ALL-l gene rearrangement and a clonal t(11;20)(p15;qll)
without cytogenetic evidence of involvement of band 1lq23
(Table 2). Similarly, another secondary AML with molecular
ALL-l gene rearrangement showed del( 1 l)(q14) by karyotype (case 12). In the child previously treated for embryonal
rhabdomyosarcoma with cyclophosphamide, ionozing radiation, and dactinomycin as the only DNA topoisomerase I1
inhibitor, whose clinical course was recently rep~rted,~'
there
was molecular but not cytogenetic evidence of involvement
of the ALL-l gene at band 1lq23 (case 13, Tables l and 2).
DISCUSSION
Secondary leukemia is a complication of effective cancer
chemotherapy with epipodophyllotoxins and other DNA to-
poisomerase I1 inhibitor^.^,^"^^ ALL and non-Hodgkin's
lymphoma are the most common primary cancers among
affected pediatric patients.".32,34,'7,38
Epipodophyllotoxin-related leukemia also occurs in children after treatment of germ
cell tumors, sarcomas, neuroblastoma, and histiocytosis
x.31.36.39 The frequency of topoisomerase I1 inhibitor-related
leukemia appears to be i n ~ r e a s i n g . ~ . ~ ~
We examined the clinical, cytogenetic, and molecular diversity in 17 cases of secondary leukemia in children who
received topoisomerase I1 inhibitors or developed secondary
leukemias typical of those associated with this therapy. Although a period of myelodysplasia often precedes the form
of secondary AML associated with alkylating agents and
irradiation, leukemias associated with epipodophyllotoxins
more commonly present as overt AML.9,32However, four
patients in this series presented with myelodysplasia rather
than overt leukemia.
Of 17 cases, 15 had cytogenetic and/or molecular involvement of chromosome band 1lq23. Molecular rearrangement
of the AML-I oncogene at chromosome band 21q22 was not
excluded in case 16, whichwas of FAB M2morphology
and negative for involvement of chromosome band llq23
by both karyotype and Southern blot
Cases with
the t(15; 17) or inv(l6) were not observed.15"'
The Southern blot results suggest that the clustering of
1lq23 breakpoints within the ALL-l gene in pediatric secondary leukemias is similar to sporadic c a ~ e s . ~The
~ - *detec~
tion of only one derivative chromosome in 6 of 14 cases with
molecular rearrangement may be consistent with interstitial
deletion of the telomeric region of ALL-l during translocation." Four of 14 cases showed occult molecular rearrangement, a somewhat higher incidence than in karyotype
negative sporadic AML.43
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3254
Most but notall t( 11;19)(q23;p13) molecular breakpoints
in sporadic infant leukemia are within the ALL-l genomic
breakpoint cluster.44 In this series, three of four t(l1; 19)
secondary leukemia breakpoints localized to the ALL-1 genomic breakpoint cluster. In case 15, the breakpoint was not
identified within the ALL-I genomic breakpoint cluster or 5'
of this region.'' In four cases of sporadic t( 11; 19)(q23;p13)
leukemia, fluorescence in situ hybridization showed I lq23
breakpoints distal to t(4; 1 l), t(9; 1 l), and t(6; 11) cases, but
involvement of the more telomeric locus, rck, has been exc l ~ d e d . ' " These
~ ~ ~ observations suggest an additional leukemia-associated gene at chromosome band 1 Iq23. PLZF,
which also mapstoband
llq23, is involved in a variant
translocation with the retinoic acid receptor-a locus in APL4X
but case 15 did not have features of APL.
Novel cytogenetic features also suggest diversity in the
pediatric DNA topoisomerase I1 inhibitor-related leukemias.
The t(9; 1 l)(p21;q23) commonly identified in cases of epipodophyllotoxin-related AML occurred in only three cases
in this series. The t(3; 1l)(q25;q23) is a variant translocation
previously described in case 6."'We determined thatthe
1 lq23 chromosomal breakage in this case was within the
ALL-l genomic breakpoint cluster. The EVII and EAP genes
are fused with AML-I at chromosome band 21q22 in variant
t(3; 21)(q26;q23) translocations in therapy-related AML and
chronic myelogenous l e ~ k e m i a . ~Whether
~.~'
a common region on chromosome 3q is involved in translocations with
both the ALL-l and AML-I genes remains to be explored.
Another variant translocation was the t(1; ll)(p32;q23) in
therapy-related MDS (case 7).
Epipodophyllotoxin-induced secondary ALL is uncommon
in both children
secondary
The
and
ALLs are
of B- or T-cell lineage and demonstrate t(4; 11) or
t( 11;16)
chromosomal translocations.'2.28,52.53
The del( 1 l)(q23) that we
identified in case 8 and mapped molecularly has not been reported in secondary ALL.
Cases 12 and 14 showing the del(ll)(ql4) or t(11;20)
(p15;qll) by karyotype had molecular rearrangements of the
ALL-l gene at band 1 lq23. There may have been complex
translocations or inversions involving chromosome 1 1, or
molecular rearrangement of ALL-l independent of the cytogenetically detectable abnormalities. Alternatively, the
l lq23 translocations may have appeared falsely in the karyotype as more proximal abnormalities of 1Iq or of 1 lp. In
sporadic leukemias with the t(9; 1l ) involving bands 1lp13
or llq13, and in leukemias with the t(11;20)(p15;qll), the
breakpoints were not explored r n ~ l e c u l a r l y . ~ ~ ~ ~ ~
The association of epipodophyllotoxins and anthracyclines with secondary leukemia is well-established.9~"~3'"9~'x
Dactinomycin without other DNA topoisomerase I1 inhibitors has not previously been associated with secondary
1 lq23
In this study, a case of secondary AML,
where the only prior DNA topoisomerase I1 inhibitor exposure was dactinomycin, was shown to have ALL-I gene
rearrangement (case 13). Also included in the sarcoma treatment were local irradiation, vincristine, and cyclophosphamide.-" This case suggests that some risk of 1 lq23 leukemia
may be associated with dactinomycin. The agent is probably
less leukemogenic than the other DNA topoisomerase I1 in-
FELIX ET AL
hibitors, as this complication has not occurred in survivors
of Wilms' tumor. It has also been proposed that the development of llq23 leukemia may be potentiated by alkylating
agents in conjunction withDNA topoisomerase I1 inhibitors.31,5R
Case 5 of t( 1 1; 19) secondary AML occurred 15 months
after the diagnosis of Hodgkin's disease thatwastreated
with carmustine, cyclophosphamide, vinblastine, procarbazine, and irradiation, a regimen that did not include a DNA
topoisomerase I1 inhibitor. Cases 5 and 13 suggest heterogeneity in the agents associated with secondary 1lq23 leukemia and the mechanism of leukemogenesis.
Whenused in conjunction with alkylating agents, epipodophyllotoxins may result in secondary AML withcharacteristic monosomies of chromosomes 5 or 7 as well as 1 lq23
chromosomal trans location^.^ Case 17 of secondary AML
after embryonal rhabdomyosarcoma treated with vincristine,
doxorubicin, cyclophosphamide, cis-platinum, etoposide,
dactinomycin, and irradiation, showed monosomies of chromosomes 5 and 7. There were two translocations, but chromosomalband llq23 was ~ninvolved.~'
Molecular ALL-1
gene rearrangement was not present.
Among 15 patients in this series with karyotypic and/
or molecular secondary 1lq23 leukemia, there was clinical,
phenotypic, morphologic, molecular, and cytogenetic heterogeneity. There are some survivors, but the outcome was most
often fatal. The clinical efficacy of DNA topoisomerase I1
interactive agents mandates a better understanding ofwhy
these drugs are associated with leukemogenic translocations.
By genomic cloning and sequencing, potential DNA topoisomerase I1 sites wereidentified in the ALL-I and AF-9
genes at a t(9; 1 1) breakpoint in sporadic AML.'" This Southern blot analysis provides the framework for further study
of the mechanism whereby drug-topoisomerase 11-DNA interactions result in translocations.
ACKNOWLEDGMENT
We thank Jean Belasco, W. Paul Bowman, Nai-Kong Cheung,
Arnold Altman, Robert Bash, Roe Wimmer, Deborah Provisor, and
George Sleight for providing patient samples and clinical information. We thank Yang Song Gu for the SKV3 5' ALL-I cDNA clone
and B I genomic DNA, Peter Nowell for cytogenetic analyses, and
Ruth Heyn and David Malkin for helpful discussion.
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1995 85: 3250-3256
ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related
leukemia in children
CA Felix, MR Hosler, NJ Winick, M Masterson, AE Wilson and BJ Lange
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