t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5′ MONOPHOSPHATE SYNTHETASE) gene

Abstract The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5′ ends and random hexamers at the 3′ ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLLexon 7 or exon 8 with the GMPS (GUANOSINE 5′-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene ofMLL on chromosome 3q and the first gene of this type in leukemia-associated translocations.

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t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5′ MONOPHOSPHATE SYNTHETASE) gene

Blood ◽

10.1182/blood.v96.13.4360.h8004360_4360_4362 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4360-4362 ◽

Cited By ~ 2

Author(s):

Linda D. Pegram ◽

Maureen D. Megonigal ◽

Beverly J. Lange ◽

Peter C. Nowell ◽

Janet D. Rowley ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Fusion Transcript ◽

Guanosine Monophosphate ◽

Chromosome Band ◽

Prior Therapy ◽

Partner Gene ◽

Acute Myeloid

The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5′ ends and random hexamers at the 3′ ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLLexon 7 or exon 8 with the GMPS (GUANOSINE 5′-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene ofMLL on chromosome 3q and the first gene of this type in leukemia-associated translocations.

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Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA- topoisomerase II

Blood ◽

10.1182/blood.v82.12.3705.bloodjournal82123705 ◽

1993 ◽

Vol 82 (12) ◽

pp. 3705-3711 ◽

Cited By ~ 7

Author(s):

HJ Super ◽

NR McCabe ◽

MJ Thirman ◽

RA Larson ◽

MM Le Beau ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Chromosome Band ◽

Dna Topoisomerase Ii ◽

Dna Topoisomerase ◽

Mll Gene ◽

Topo Ii ◽

Acute Myeloid

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

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HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]

Blood ◽

10.1182/blood.v81.12.3197.3197 ◽

1993 ◽

Vol 81 (12) ◽

pp. 3197-3203 ◽

Cited By ~ 113

Author(s):

SP Hunger ◽

DC Tkachuk ◽

MD Amylon ◽

MP Link ◽

AJ Carroll ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Myelogenous Leukemia ◽

Chromosome Band ◽

11Q23 Abnormalities ◽

Acute Myeloid ◽

Secondary Leukemias

Abstract Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.

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HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]

Blood ◽

10.1182/blood.v81.12.3197.bloodjournal81123197 ◽

1993 ◽

Vol 81 (12) ◽

pp. 3197-3203 ◽

Cited By ~ 7

Author(s):

SP Hunger ◽

DC Tkachuk ◽

MD Amylon ◽

MP Link ◽

AJ Carroll ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Myelogenous Leukemia ◽

Chromosome Band ◽

11Q23 Abnormalities ◽

Acute Myeloid ◽

Secondary Leukemias

Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.

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Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA- topoisomerase II

Blood ◽

10.1182/blood.v82.12.3705.3705 ◽

1993 ◽

Vol 82 (12) ◽

pp. 3705-3711 ◽

Cited By ~ 206

Author(s):

HJ Super ◽

NR McCabe ◽

MJ Thirman ◽

RA Larson ◽

MM Le Beau ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Chromosome Band ◽

Dna Topoisomerase Ii ◽

Dna Topoisomerase ◽

Mll Gene ◽

Topo Ii ◽

Acute Myeloid

Abstract Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

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The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽

10.1182/blood-2010-08-301713 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2137-2145 ◽

Cited By ~ 216

Author(s):

Sabine Kayser ◽

Konstanze Döhner ◽

Jürgen Krauter ◽

Claus-Henning Köhne ◽

Heinz A. Horst ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Negative Impact ◽

Primary Malignancy ◽

De Novo Aml ◽

The Impact ◽

Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

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Coexpression of NUP98/TOP1 and TOP1/NUP98 in de novo Acute Myeloid Leukemia with t(11;20)(p15;q12) and t(2;5)(q33;q31)

Cytogenetic and Genome Research ◽

10.1159/000458168 ◽

2016 ◽

Vol 150 (3-4) ◽

pp. 287-292

Author(s):

Katsuya Yamamoto ◽

Yosuke Minami ◽

Kimikazu Yakushijin ◽

Yu Mizutani ◽

Yumiko Inui ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Fusion Gene ◽

Fusion Transcript ◽

Fish Analysis ◽

Balanced Translocation ◽

Cytogenetic Aberration ◽

De Novo Aml ◽

Acute Myeloid

The t(11;20)(p15;q11∼12) translocation is a very rare but recurrent cytogenetic aberration that occurs in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). This translocation was shown to form a fusion gene between NUP98 at 11p15 and TOP1 at 20q12. Here, we describe a new case of de novo AML M2 with t(11;20) which was associated with another balanced translocation. An 81-year-old man was admitted to undergo salvage therapy for relapsed AML. G-banding and spectral karyotyping showed 46,XY,t(2;5)(q33;q31),t(11;20)(p15;q12)[20]. Expression of the NUP98/TOP1 fusion transcript was confirmed: NUP98 exon 13 was in-frame fused with TOP1 exon 8. The reciprocal TOP1/NUP98 fusion transcript was also detected: TOP1 exon 7 was fused with NUP98 exon 14. After achieving hematological complete remission, the karyotype converted to 46,XY,t(2;5)(q33;q31)[19]/46,sl,t(11;20)(p15;q12)[1]. FISH analysis demonstrated that the 5q31 breakpoint of t(2;5) was centromeric to EGR1. In all 10 cases described in the literature, the NUP98 exon 13/TOP1 exon 8 fusion transcript was expressed, indicating that it may be responsible for the pathogenesis of MDS/AML with t(11;20). On the other hand, the TOP1/NUP98 transcript was coexpressed in 4 cases of de novo AML, but not in 3 cases of therapy-related MDS. Thus, this reciprocal fusion may be associated with progression to AML.

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The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation

Blood ◽

10.1182/blood.v83.10.2780.2780 ◽

1994 ◽

Vol 83 (10) ◽

pp. 2780-2786 ◽

Cited By ~ 252

Author(s):

J Pedersen-Bjergaard ◽

JD Rowley

Keyword(s):

Acute Myeloid Leukemia ◽

Chromosome Aberrations ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Alkylating Agents ◽

Dna Topoisomerase Ii ◽

Dna Topoisomerase ◽

Chromosome Material ◽

Acute Myeloid

Abstract Two general types of clonal chromosome abnormality are observed in de novo acute myeloid leukemia (AML): the unbalanced aberrations with visible gain or loss of chromosome material and the balanced aberrations without such visible gain or loss. AML can be induced by therapy with cytostatic drugs and radiation. The alkylating agents reacting directly with DNA induce AML which often presents as myelodysplasia with unbalanced aberrations, primarily loss of chromosome material. Cytostatic agents targeting DNA-topoisomerase II, frequently administered together with alkylating agents or cisplatin, induce the same type of leukemia. In addition, they often induce another type with a more rapid onset and with specific balanced chromosome aberrations rarely observed after therapy with alkylating agents alone. All of the most important chromosome aberrations found in de novo AML are now also found in therapy-related AML (t-AML); thus, t- AML may serve as a model in the search for mechanisms leading to the development of AML in general. Unbalanced chromosome aberrations with partial deletions or with loss of whole chromosomes may develop as a result of alkylation of DNA or other cellular targets. Balanced chromosome aberrations, on the other hand, may develop as illegitimate recombinations related to the activity of DNA-topoisomerase II. The balanced translocations contribute to malignant transformation by the formation of abnormal chimeric genes, whereas deletions may contribute by the loss of putative tumor suppressor genes. In either situation, the chromosome changes provide the altered cells with a proliferative advantage compared with normal cells.

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A Novel and Cytogenetically Cryptic t(7;21)(q36.1;q22) Disrupting RUNX1 in Acute Myeloid Leukemia

Cytogenetic and Genome Research ◽

10.1159/000494452 ◽

2018 ◽

Vol 156 (3) ◽

pp. 140-143 ◽

Cited By ~ 1

Author(s):

Adriana Zámečníkova ◽

Soad Al Bahar

Keyword(s):

Acute Myeloid Leukemia ◽

Transcription Factor ◽

Myeloid Leukemia ◽

De Novo ◽

Hematologic Malignancies ◽

Transcription Factor Gene ◽

Factor Gene ◽

The Third ◽

Partner Gene ◽

Acute Myeloid

Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report here a novel RUNX1 partner gene, KMT2C (MLL3), in a patient with de novo acute myeloid leukemia, having a novel and cytogenetically cryptic t(7;21)(q36.1;q22) leading to disruption of RUNX1 and KMT2C. This is the third cryptic RUNX1 rearrangement in myeloid and the fourth in hematologic malignancies.

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