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Clinical Cancer Research Vol. 10, 5355-5360, August 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

TEL Deletion Analysis Supports a Novel View of Relapse in Childhood Acute Lymphoblastic Leukemia

Jan Zuna1,2, Anthony M. Ford1, Martina Peham3, Naina Patel4, Vaskar Saha4, Cornelia Eckert5, Joachim Köchling5, Renate Panzer-Grümayer3, Jan Trka2 and Mel Greaves1

1 Leukemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom; 2 Childhood Leukaemia Investigation Prague (CLIP), Department of Paediatric Haematology and Oncology, 2nd Medical School, Charles University, Prague, Czech Republic; 3 Children’s Cancer Research Institute and St Anna Kinderspital, Vienna, Austria; 4 Cancer Research UK Children’s Cancer Group, Royal London Hospital, London, United Kingdom; and 5 Charite, Department of Paediatric Oncology/Haematology, Humboldt-University, Campus Virchow-Klinikum, Berlin, Germany

ABSTRACT

Purpose: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.

Experimental Design: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.

Results: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.

Conclusions: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.

INTRODUCTION

TEL-AML1 (ETV6-RUNX1) fusion, via the t(12;21)(p13;q22) chromosomal translocation is a common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (ALL) present in ~20 to 25% of cases (1, 2, 3, 4, 5) . Studies on identical twins with concordant ALL (6, 7, 8) and retrospective scrutiny of neonatal blood spots (Guthrie cards; refs. 8, 9, 10, 11 ) have provided evidence that TEL-AML1 often arises prenatally, possibly as a first or initiating event. A corollary of these data are that a "preleukemic" clone with TEL-AML1 can persist postnatally for extended periods, up to ~14 years (7) and that at least one other postnatal genetic event is required for overt leukemia. The majority of cases of TEL-AML1-positive ALL have deletion of the nontranslocated TEL allele at diagnosis (12, 13, 14) . TEL deletions vary in size from 10 kb to >10 megabases as judged by microsatellite loss of heterozygosity (LOH) but the minimally deleted regions always affect at least some part of the TEL transcription framework (15 , 16) . Studies on both singletons (12 , 14) and twins (8) with ALL indicate that such TEL deletions are subclonal or secondary to TEL-AML1 and almost certainly postnatal. Candidate preleukemic clones in normal cord blood with TEL-AML1 fusions retain the normal TEL allele (17) . Whether other genetic changes in addition to TEL deletion, e.g., kinase mutations (18) , are necessary for the clinical development of ALL remains to be established.

These data throw light on the natural history of childhood ALL (19) , but they also have clinical implications. One particular issue is whether the putative preleukemic clone with TEL-AML1 fusion but no TEL deletion responds to therapy as does the dominant clone of overt leukemic blasts at diagnosis. One possibility is that they might persist in some patients and, in so doing, provide a reservoir of "at risk" cells for later independent second hits, i.e., TEL deletion and/or other events that would precipitate a de novo ALL masquerading as relapse. The plausibility of this unconventional interpretation of "late" relapse in ALL is supported by the clinical responsiveness of many cases of late or off-treatment ALL relapses (20) . In a small pilot study of this issue, we reported that in two patients with off-treatment relapse of TEL-AML1-positive ALL, the TEL deletions that were present at relapse had different genomic boundaries and were smaller than the deletions observed at diagnosis (21) . This result was possible only if TEL deletions were secondary and further suggested that the dominant clone at diagnosis might not be that which appeared in relapse.

In view of the potential clinical importance of these preliminary data, we have carried out a systematic analysis of TEL deletion by microsatellite mapping in a series of patients with TEL-AML1-positive ALL in relapse. Importantly, in addition to the TEL deletion analysis, in this series we have sought confirmation of the clonal relatedness of diagnostic and relapse clones via sequence analysis of rearrangements of immunoglobulin and T-cell receptor (TCR) genes and, in some cases, genomic TEL-AML1 fusion.

PATIENTS, MATERIALS, AND METHODS

Patients.
Clinical features of the 19 analyzed patients with relapsed TEL-AML1-positive ALL are summarized in Table 1Citation . The patients were selected on the basis of DNA availability. Presentation and relapse samples were available from 17 patients, and samples from 2 children were analyzed at first and second relapse. A remission DNA sample was obtainable in 11 cases. In the remaining eight patients, only TEL deletion in samples from presentation and relapse (or first and second relapse) could be compared. Patients with Unique Patient Numbers (UPN) 1 to 16 were treated according to Berlin-Frankfurt-Munster (BFM)-based protocols, patients UPN 17 to 19 according to Medical Research Council (MRC), United Kingdom, ALL-based protocols. None of the patients underwent allogeneic hematopoietic stem cell transplantation before first relapse (or before second relapse for patients UPN 14 and 19). Informed consent was obtained from each subject or subject’s guardian.


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  		Table 1 Clinical characteristics and TEL status of analysed patients

 
Microsatellite Mapping of TEL Deletions.
For the microsatellite mapping, we used the method described by Baccichet and Sinnett (22) with some additional markers on 12p. The list of markers included D12S352, D12S94, D12S356, D12S336, D12S77, D12S1697, D12S1095, D12S89, TEL/KIPca2, D12S98, TEL/KIPca3, TEL/KIPca3, D12S391, TEL/KIPca5, D12S358, D12S320, D12S364, D12S269, D12S308, D12S62, D12S70, D12S310, and D12S363. Sequences of primers are available at The Genome Database (http://gdbwww. gdb.org/).6 Each PCR reaction contained 8 ng of genomic DNA. Final concentration of each dNTP was 50 µmol/L, and [{alpha}-32P]dCTP at a final concentration of 37 kBq was added. After denaturation for 3 minutes at 94°C, amplification was performed for 28 cycles at 94°C for 30 seconds, at 55°C for 60 seconds, and at 72°C for 60 seconds. Before electrophoresis on 6% polyacrylamide gels containing 7 mol/L Urea, samples were denatured in 98% formamide, 0,02% bromphenol blue, and 10 mmol/L EDTA by heating to 90°C for 3 minutes; the samples were then chilled on ice. LOH was scored if the relative intensity of one allele was lost or diminished in the same patient either at presentation or at relapse when compared with remission DNA.

Immunoreceptor Gene Rearrangement Analysis.
In bone marrow samples, we examined the pattern of immunoglobulin/TCR gene rearrangements using 18 screening PCR reactions (23 , 24) . The set of reactions covers the vast majority (>90%) of immunoglobulin heavy chain (IgH), Ig{kappa}, TCR-{delta} and TCR-{gamma} gene rearrangements in B-cell precursor ALL. The primers and PCR conditions were published elsewhere (23 , 24) . To reliably distinguish clonal PCR products from polyclonal, we performed heteroduplex analyses of fragments using polyacrylamide gels (25) . Homoduplexes were cut from the gel, were reamplified, and were sequenced. Sequences of rearrangements at presentation and relapse were compared.

Characterization of TEL-AML1 Fusion at DNA Level.
Amplification of the genomic breakpoint fusion sequences for TEL-AML1 at relapse was performed by long-range PCR using conditions and primers previously described (8 , 26) . Primers TEL6B and TEL8B were used in combination with each of 11 AML1 primers. The breakpoint sequence was obtained through restriction analysis by primer walking and sequencing. Patient-specific primers for amplification of fusion breakpoints were designed so that PCR yielded a product of 130 to 300 base-pairs. DNA from presentation material was then amplified using these primers, and resulting products were sequenced to confirm identity with TEL-AML1 intronic fusion in relapse samples.

RESULTS

Deletions of the Second TEL Allele.
We analyzed bone marrow samples of 19 patients with relapsed TEL-AML1-positive ALL. In 11 patients in which remission DNA was available, we were able to assess microsatellite markers within the 12p locus and screen the informative loci (heterozygous) for LOH at presentation and relapse (at first and second relapse in patient UPN 19). In the remaining eight patients, remission samples were not available. Thus, we were able to compare only the diagnostic and relapse samples in each patient (first and second relapse samples in patient UPN 14), and LOH was determined only at markers where the two samples differed.

The results of the presentation versus relapse analyses can be divided into four groups (Table 1)Citation . Group U (unchanged) consists of five patients with an apparent similar pattern of LOH analysis at both presentation and relapse (patients 3, 6, 12, 17, and 18). Patients from group L (larger at relapse; n = 7; patients 1, 2, 7, 8, 13, 15, and 16) had a larger deletion at relapse than in the presentation sample. LOH at relapse was longer by one to six markers in these patients, compared with diagnostic material. Group S (shorter at relapse) comprises three patients (patients 4, 14, and 19), in which the deletion at relapse was shorter than the deletion seen at presentation. We found at least one informative microsatellite marker at first relapse or second relapse that was deleted at either original presentation or first relapse, respectively. Group N (noninformative) includes four cases in which LOH data were not informative. Illustrative examples of patients from each group are shown in Fig. 1Citation .



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  		Fig. 1. Microsatellite analysis results. Illustrative examples of patients from each TEL deletion group are labeled as follows: L, larger deletion at relapse; U, unchanged; S, smaller deletion at relapse; N, noninformative. {permzspch098}, heterozygous; {permzspch097}, deleted (LOH); {zdf01604315200s1}, noninformative. (PRES, presentation; REM, remission; REL, relapse; SCDR, shortest commonly deleted region; cent, centromere.)

 
Immunoglobulin/TCR Genes Rearrangements.
As a test of clonality, the analysis of immunoreceptor genes rearrangements was performed in 16 patients (UPN 1–16). The data from cases 1 to 6 and 14 are shown in Table 2Citation , and detailed data of cases 7 to 13 and 15 to 16 have been published elsewhere (27) . All of the clonal rearrangements detected and sequenced in relapse samples of patients UPN 1, 3, 6, 7, 9, 10, 12, and 13 were also shown to be present as major rearrangements in the diagnostic samples. Correspondingly, patient UPN 14 had three clonal rearrangements detected at second relapse, all of which were also present in the first-relapse sample. One additional rearrangement in the first-relapse sample was detected in this patient. Patient UPN 5 had two rearrangements maintained between presentation and diagnosis, and another two rearrangements were changed but, nonetheless, seem related between the two time points (one IgH rearrangement with identical (N)-D-J sequence and different VH segment and another IgH rearrangement with identical D-J joining and VH segment but different V-(N)-D fusion region). Patients UPN 2, 4, 8, 11, and 16 had at least one "new" clonal rearrangement at relapse compared with the screening performed on the presentation sample, but other rearrangements were preserved between presentation and relapse. Patient UPN 15 showed a very different rearrangement pattern between diagnosis and relapse, with four rearrangements detected at presentation and two different rearrangements at relapse. However, in this patient both of the new rearrangements found at relapse were successfully amplified from the presentation DNA using patient-specific primers at level 5 x 10–4 (detailed analysis of immunoglobulin/TCR rearrangements of this patient was published previously; ref. 28 ).


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  		Table 2 Immunoreceptor gene rearrangements of patients UPN 1 to 6 and 14 at diagnosis and relapse

 
TEL-AML1 Intronic Fusion.
In five relapse samples (UPN 3, 4, 15, 18, and 19) we identified the patient-specific TEL-AML1 genomic fusion sequence. In all of these five patients, we amplified an identical PCR product from the presentation material as confirmed by sequencing analysis. The intensity of the diagnostic product on an agarose gel was comparable with that observed in the relapse sample in all cases. These data indicate that the relapse had arisen from the same preleukemic clone present at diagnosis.

DISCUSSION

This molecular scrutiny of clonal relatedness in relapsed versus diagnostic TEL-AML1 ALL was designed to confirm that the same or related clones are involved and to assess the consistency with which TEL deletions alter in relapse compared with diagnosis (21) . We previously argued that the appearance of smaller TEL deletions in late relapses (i.e., off treatment) of TEL-AML1 might reflect a new ALL generated from a persistent preleukemic clone rather than a conventional relapse (21) . One attraction of this idea was that it might rationalize the otherwise surprising clinical observation that late relapses of B-cell precursor/common ALL are often as therapeutically sensitive as ALLs of first diagnosis, with sustained remissions and cures achievable in most cases (20) .

In all but one (15 of 16) cases of relapse in which we evaluated for immunoglobulin/TCR rearrangements, there was definitive molecular evidence that a related clone was involved, i.e., at least one clonotypic rearrangement was shared. In the remaining case (UPN 15) and also in another four cases, we were able to evaluate and confirm that the clonotypic genomic TEL-AML1 fusion sequence, believed to mark the initiated preleukemic clone (8 , 17 , 28) , was identical at relapse and diagnosis. A prediction of the hypothesis is that TEL deletions, as common but secondary events, should be different in their genomic boundaries at diagnosis and relapse. In practice, the only result that is unequivocal in this respect is relapse with a smaller TEL deletion (three cases described here). Relapse cases with a larger deletion would also be anticipated to occur, and the seven cases described here are, therefore, compatible with this view; however, we cannot exclude the possibility that larger deletions arise by attrition of boundaries of prior smaller deletions. Cases with identical TEL deletions at diagnosis and relapse may contradict the hypothesis and one third (5 of 15) of our informative patients had this feature. This could indicate that the dominant clone at diagnosis reappeared in relapse. A caveat here is, however, that the genomic boundaries are defined only with respect to the available microsatellite markers for which the patient is heterozygous. Boundary differences of a modest size (i.e., <0.5 cM) would be undetected. In a recent study, Takeuchi et al. (29) found that LOH at loci other than 12p/TEL were also divergent between diagnosis and relapse of childhood ALL, and, in some cases, a deletion present at diagnosis was not evident in relapse cells. The authors suggested that this might indicate the emergence of relapse from a small subpopulation of cells present at diagnosis.

The conclusion from these studies is therefore that late relapse in childhood ALL with TEL-AML1 does represent, as anticipated, emergence of a related subclone, but in some cases, it is a different dominant clone from that seen at initial diagnosis. Clearly, this result indicates persistence of a subclone in complete remission possibly at levels undetectable in PCR-based minimal residual disease screening. One possibility is that the "different" subclone in relapse is present as a very minor subclone at diagnosis, evades elimination by therapy, and re-emerges over time, particularly after cessation of therapy. Evidence for this is now available from immunoglobulin/TCR analysis, which indicates that dominant TEL-AML1-positive clones in relapse may be present at low levels (10–4 to 5 x 10–3 total) at diagnosis and are poorly or only slowly responsive to induction chemotherapy (27 , 28) . This is compatible with the view that these cells represent the reservoir of relatively drug-resistant preleukemic cells (28) . We assume that these cells may remain in a dormant state during hematologic remission, may be gradually lost, or, if suffering a second hit (i.e., TEL deletion or other), will amplify as an overt ALL cell population in later "relapse" (see Fig. 2Citation ). This interpretation is difficult to prove unequivocally but accords best with the clinical observations and parallels similar views on the persistence of AML1-ETO-positive preleukemic clones in remission of acute myeloid leukemia (30, 31, 32) . The results of the study are influential for the understanding of pathogenesis and natural history of childhood ALL (33) . If correct, they change our understanding of the biology of remission and relapse and may have possible implications for the detection of minimal residual disease. Furthermore, the proposed interpretation might influence the treatment approach to the TEL-AML1-positive relapses.



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  		Fig. 2. Conventional (A) and novel (B) models for the recurrence of TEL/AML1-positive leukemia. According to the novel model, even if the dominant diagnostic clone is completely eradicated, the preleukemic TEL/AML1-positive cells are still present and susceptible to an independent second hit [TEL deletion (TELdel)] that can precipitate a de novo leukemia masquerading as relapse. (Dx, diagnosis; MRD, minimal residual disease.)

 

FOOTNOTES

Grant support: Supported by grant GACR 301/P041, projects of MSMT-CR 111300001 and 111300003, the Österreichische Kinder-krebshilfe, and a specialist program grant from the Leukaemia Research Fund, United Kingdom (M. Greaves).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Jan Zuna, Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Medical School, Charles University Prague, V Uvalu 84, 150 06, Prague 5, Czech Republic. Phone: 420-224432280; Fax: 420-224432268; E-mail: jan.zuna{at}lfmotol.cuni.cz

6 Internet address for the Genome database is http://gdbwww.gdb.org/. Back

Received 3/26/04; accepted 4/21/04.

REFERENCES

  1. Borkhardt A, Cazzaniga G, Viehmann S, et al Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster Study Group. Blood, 90: 571-7, 1997.[Abstract/Free Full Text]
  2. McLean TW, Ringold S, Neuberg D, et al TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood, 88: 4252-8, 1996.[Abstract/Free Full Text]
  3. Romana SP, Poirel H, Leconiat M, et al High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood, 86: 4263-9, 1995.[Abstract/Free Full Text]
  4. Shurtleff SA, Buijs A, Behm FG, et al TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia, 9: 1985-9, 1995.[Medline]
  5. The United Kingdom Childhood Cancer study: objectives, materials and methods. UK Childhood Cancer Study Investigators. Br J Cancer, 82: 1073-102, 2000.[CrossRef][Medline]
  6. Ford AM, Bennett CA, Price CM, Bruin MC, Van Wering ER, Greaves M. Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci USA, 95: 4584-8, 1998.[Abstract/Free Full Text]
  7. Wiemels JL, Ford AM, Van Wering ER, Postma A, Greaves M. Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. Blood, 94: 1057-62, 1999.[Abstract/Free Full Text]
  8. Maia AT, Ford AM, Jalali GR, et al Molecular tracking of leukemogenesis in a triplet pregnancy. Blood, 98: 478-82, 2001.[Abstract/Free Full Text]
  9. Hjalgrim LL, Madsen HO, Melbye M, et al Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia. Br J Cancer, 87: 994-9, 2002.[CrossRef][Medline]
  10. McHale CM, Wiemels JL, Zhang L, et al Prenatal origin of TEL-AML1-positive acute lymphoblastic leukemia in children born in California. Genes Chromosomes Cancer, 37: 36-43, 2003.[CrossRef][Medline]
  11. Wiemels JL, Cazzaniga G, Daniotti M, et al Prenatal origin of acute lymphoblastic leukaemia in children. Lancet, 354: 1499-503, 1999.[CrossRef][Medline]
  12. Cave H, Cacheux V, Raynaud S, et al ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia. Leukemia (Baltimore), 11: 1459-64, 1997.
  13. Kempski H, Chalker J, Chessells J, et al An investigation of the t(12;21) rearrangement in children with B-precursor acute lymphoblastic leukaemia using cytogenetic and molecular methods. Br J Haematol, 105: 684-9, 1999.[CrossRef][Medline]
  14. Raynaud S, Cave H, Baens M, et al The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood, 87: 2891-9, 1996.[Abstract/Free Full Text]
  15. Aissani B, Sinnett D. Fine physical and transcript mapping of a 1.8 Mb region spanning the locus for childhood acute lymphoblastic leukemia on chromosome 12p12.3. Gene (Amst), 240: 297-305, 1999.[CrossRef][Medline]
  16. Baens M, Wlodarska I, Corveleyn A, Hoornaert I, Hagemeijer A, Marynen P. A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p). Genomics, 56: 40-50, 1999.[CrossRef][Medline]
  17. Mori H, Colman SM, Xiao Z, et al Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA, 99: 8242-7, 2002.[Abstract/Free Full Text]
  18. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer, 2: 502-13, 2002.[CrossRef][Medline]
  19. Greaves M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur J Cancer, 35: 1941-53, 1999.
  20. Seeger K, Stackelberg AV, Taube T, et al Relapse of TEL-AML1–positive acute lymphoblastic leukemia in childhood: a matched-pair analysis. J Clin Oncol, 19: 3188-93, 2001.[Abstract/Free Full Text]
  21. Ford AM, Fasching K, Panzer-Grumayer ER, Koenig M, Haas OA, Greaves MF. Origins of "late" relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes. Blood, 98: 558-64, 2001.[Abstract/Free Full Text]
  22. Baccichet A, Sinnett D. Frequent deletion of chromosome 12p12.3 in children with acute lymphoblastic leukaemia. Br J Haematol, 99: 107-14, 1997.[CrossRef][Medline]
  23. Pongers-Willemse MJ, Seriu T, Stolz F, et al Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: report of the BIOMED-1 CONCERTED ACTION: investigation of minimal residual disease in acute leukemia. Leukemia (Baltimore), 13: 110-8, 1999.
  24. Szczepanski T, Willemse MJ, van Wering ER, van Weerden JF, Kamps WA, van Dongen JJ. Precursor-B-ALL with D(H)-J(H) gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14. Leukemia (Baltimore), 15: 1415-23, 2001.
  25. Langerak AW, Szczepanski T, van der Burg M, Wolvers-Tettero IL, van Dongen JJ. Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations. Leukemia (Baltimore), 11: 2192-9, 1997.
  26. Wiemels JL, Greaves M. Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res, 59: 4075-82, 1999.[Abstract/Free Full Text]
  27. Peham M, Konrad M, Harbott J, Konig M, Haas OA, Panzer-Grumayer ER. Clonal variation of the immunogenotype in relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia indicates subclone formation during early stages of leukemia development. Genes Chromosomes Cancer, 39: 156-60, 2004.[CrossRef][Medline]
  28. Konrad M, Metzler M, Panzer S, et al Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone. Blood, 101: 3635-40, 2003.[Abstract/Free Full Text]
  29. Takeuchi S, Seriu T, van Dongen JJ, et al Allelotype analysis in relapsed childhood acute lymphoblastic leukemia. Oncogene, 22: 6970-6, 2003.[CrossRef][Medline]
  30. Kusec R, Laczika K, Knobl P, et al AML1/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. Leukemia (Baltimore), 8: 735-9, 1994.
  31. Miyamoto T, Nagafuji K, Akashi K, et al Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood, 87: 4789-96, 1996.[Abstract/Free Full Text]
  32. Nucifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood, 82: 712-5, 1993.[Abstract/Free Full Text]
  33. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer, 3: 639-49, 2003.[CrossRef][Medline]



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