Topoisomerase II Inhibitor-Related Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitor ◽  
Acute Myeloid

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

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3705-3711 ◽  
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.

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

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3197-3203 ◽  
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.

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

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
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.

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

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4360-4362 ◽  
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.

Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 1909-1912 ◽  
Author(s):  
Jens Pedersen-Bjergaard ◽  
Mette K. Andersen ◽  
Debes H. Christiansen ◽  
Claus Nerlov
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosome Aberrations ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
The Other ◽  
Genetic Pathways ◽  
Topoisomerase Ii Inhibitors ◽  
Acute Myeloid

Abstract Therapy-related acute myeloid leukemia (t-AML) in most cases develops after chemotherapy of other malignancies and shows characteristic chromosome aberrations. Two general types of t-AML have previously been identified. One type is observed after therapy with alkylating agents and characteristically presents as therapy-related myelodysplasia with deletions or loss of the long arms of chromosomes 5 and 7 or loss of the whole chromosomes. The other type is observed after therapy with topoisomerase II inhibitors and characteristically presents as overt t-AML with recurrent balanced chromosome aberrations. Recent research suggests that these 2 general types of t-AML can now be subdivided into at least 8 genetic pathways with a different etiology and different biologic characteristics.

scholarly journals Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Andrew P. Michelson ◽  
Shannon McDonough ◽  
Cheryl L. Willman ◽  
Eric R. Koegle ◽  
John E. Godwin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Topoisomerase Ii Α ◽  
Acute Myeloid

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

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2780-2786 ◽  
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.

Characterization of CEBPA Mutations in Acute Myeloid Leukemia in Taiwan - Most Patients with CEBPA Mutations Have Biallelic Mutations and Show a Distinct Immunophenotype of the Leukemic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4321-4321
Author(s):  
Liang In Lin ◽  
Chien Yuan Chen ◽  
Dong Tsamn Lin ◽  
You Chia Yeh ◽  
Hwei Fang Tien
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Normal Karyotype ◽  
Leukemic Cells ◽  
Intermediate Risk ◽  
Hla Dr ◽  
Cebpa Mutations ◽  
Biallelic Mutations ◽  
Acute Myeloid

Abstract The transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) encoded by the CEBPA gene, is crucial for the differentiation of immature granulocytes. Diminished or abnormal C/EBPa activity resulting from CEBPA gene mutations is widely known to contribute to the transformation of myeloid progenitors via reduction of their differentiation potential. The CEBPA mutations have been detected in approximately 7% of total acute myeloid leukemia (AML) and in 15% of those with intermediate-risk cytogenetics or those with normal karyotype. However, the age distribution of the patients with the CEBPA mutations and the immunophenotype of their leukemic cells are not known. Sequential studies of the CEBPA gene in AML patients are also limited. In this study, 104 patients with de novo acute myeloid leukemia (AML) were evaluated for the CEBPA mutation by direct sequencing. Excluding the silent mutations, 16 (15%) of the total 104 AML patients, 15 (25%) of the 61 patients with intermediate-risk cytogenetics and 11 (35%) of the 31 patients with normal karyotype showed CEBPA mutations, frequencies higher than those reported in the West. Further cloning and subsequent nucleotide sequence analysis revealed that 14 patients had heterozygous biallelic mutations: 11 had mutations involving both the N-terminal transactivation domain (TAD) and the C-terminal basic leucine zipper domain (bZIP) and three, in either the TAD region or the bZIP region. The remaining two patients had only one allele mutation in the TAD1 region. Most mutations in TAD region were repeat-number changes of simple sequence repeats and those in bZIP region were internal tandem duplications. Sequence analysis revealed that in the region spanning the bZIP mutations, there was hot spot for concensus topoisomerase II sites, which has also been shown in other AML-related mutations FLT3-ITD and MLL duplication. All but one patient with CEBPA mutations had M1 or M2 subtype of AML. The patients with CEBPA mutations had significantly higher incidences of CD7 (73%), CD15 (100%), CD34 (93%) and HLA-DR (93%) expression than others and the majority of them showed a distinct immunophenotype of the leukemic cells: HLA-DR+ CD7+ CD13+ CD14− CD15+ CD33+ CD34+. The incidence of the CEBPA mutation in children with AML was similar to that in adults. The CEBPA mutation was serially analyzed in 27 patients; the mutations disappeared at CR, but reappeared at relapse. No one developed novel mutation during the follow-up period. In conclusion, the CEBPA mutation may play an important role in the development, but not progression, of AML. The patients with the CEBPA mutations showed a distinct immunophenotype of the leukemic cells. Potential topoisomerase II cleavage sites locating in the bZIP region were first reported and we propose that this is relevant to the process of illegitimate recombination generating the internal tandem duplication pattern of bZIP mutations.

FLAG ± Idarubicin Compared with 7+3 As Initial Induction for Secondary Acute Myeloid Leukemia: A Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4330-4330
Author(s):  
Jenny Li ◽  
Mandy L Gatesman ◽  
Ashley M Newland ◽  
Roy T Sabo ◽  
Prithviraj Bose
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
Neutrophil Recovery ◽  
Secondary Aml ◽  
Topoisomerase Ii Inhibitors ◽  
Secondary Outcomes ◽  
Acute Myeloid

Abstract Abstract 4330 Objective: Acute myeloid leukemia (AML) that arises from an antecedent hematologic disorder (most often myelodysplastic syndrome, MDS) or that is related to prior chemotherapy (therapy-related AML, t-AML) carries a poor prognosis. Secondary AML occurs in 16–50% of patients with MDS and in <5% of patients previously treated with alkylating agents or topoisomerase II inhibitors. Although 50–70% of patients with de novo AML achieve complete remission (CR) with conventional induction chemotherapy (i.e., cytarabine plus an antracycline, “7+3”), secondary AML is more resistant to such treatment (40–50% CR rate). This has led to the use in some centers of alternative induction regimens such as FLAG (fludarabine, cytarabine, filgrastim) ± idarubicin (Ida) in patients with secondary AML. FLAG ± Ida has been used in patients with relapsed, high-risk MDS and in relapsed/refractory AML, and has an overall CR rate of 33% when used first-line for secondary AML (Clavio M et al. Leuk Lymphoma 2001 Jan; 40(3–4):305-13). There is currently no published data directly comparing 7+3 to FLAG ± Ida in this setting. The present study was undertaken to compare the effectiveness and safety of FLAG ± Ida and 7+3 induction regimens in patients with secondary AML. Methods: A retrospective medical record review was conducted between January 1, 2007 and September 30, 2011 of all patients with AML aged ≥18 years seen at our institution who had either cytogenetic abnormalities commonly associated with MDS or had received prior alkylating agents or topoisomerase II inhibitors, and received either FLAG ± Ida or 7+3 for initial treatment of secondary AML. Patients with chronic myelogenous leukemia in blast crisis were excluded. The primary outcome was the CR rate after induction chemotherapy. Secondary outcomes were 30-day mortality, hospital and intensive care unit (ICU) length of stay (LOS), sources and types of infections, antibiotic usage, and time to neutrophil recovery. Fisher's exact test was used to compare categorical outcomes (CR, documented infections) between groups. Kaplan-Meier curves and corresponding log-rank tests were used for time-to-event outcomes (hospital stay, ICU days, neutrophil recovery). Results: 291 charts were reviewed. 48 patients were found to be eligible and were included in the final analysis. There were no significant differences in baseline demographic characteristics between the two treatment groups, with the exception of AML transformation from MDS being more prevalent in the FLAG ± Ida group (Table I). There were no significant differences in CR rates, 30-day mortality, or hospital LOS between the two groups (Table II). 7+3 was associated with a shorter ICU LOS (0.2 ± 0.7 days vs 2.3 ± 6.8 days, p=0.04) but a greater number of days of antibiotic therapy (56.7 ± 36.3 vs 33.6 ± 31.1, p=0.03), while FLAG ± Ida was associated with a shorter time to neutrophil recovery compared with 7+3 (20.6 ± 4.4 days vs 25.8 ± 7.9 days, p=0.01). Conclusion: In this retrospective study, we found no difference in efficacy between 7+3 and FLAG ± Ida when used as initial induction therapy for patients with secondary AML. Limitations of this study include its retrospective nature, the small sample size and lack of power to detect differences between the groups for both primary and secondary outcomes. A prospectively designed trial is warranted before one regimen can be recommended over the other. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document