scholarly journals Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 712-715 ◽  
Author(s):  
G Nucifora ◽  
RA Larson ◽  
JD Rowley
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Fusion Transcript ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
First Relapse ◽  
Acute Myeloid

Abstract The translocation between chromosomes 8 and 21, t(8;21) (q22;q22), is the most frequent abnormality in acute myeloid leukemia (AML) with French-American-British type M2 (FAB-M2) morphology. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO on chromosome 8. The rearrangement of the two chromosomes results in a fusion gene and in the production of a consistent fusion transcript on the der(8) chromosome. We have used oligonucleotide primers derived from both sides of the fusion cDNA junction and reverse transcription-polymerase chain reaction (RT-PCR) to analyze six AML-M2 patients with a t(8;21) during various stages of their disease. Two patients studied at diagnosis and one studied at first relapse are alive off therapy and in continuous complete remission for 83 to 94 months. We have detected the AML/ETO fusion transcript in recent peripheral blood samples from each of them. Three other patients also had a fusion transcript detected after 1 to 4 months in remission. Two of these patients subsequently relapsed and died whereas the third patient is alive and in continuous complete remission 70 months later. Thus, our preliminary data suggest that cells with the translocation are still circulating in t(8;21) patients in long-term remission. This finding raises serious questions regarding the interpretation of positive results obtained only with this technique that may not be suitable to decide appropriate further treatment for patients in clinical remission.

scholarly journals Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 712-715 ◽  
Author(s):  
G Nucifora ◽  
RA Larson ◽  
JD Rowley
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Fusion Transcript ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
First Relapse ◽  
Acute Myeloid

The translocation between chromosomes 8 and 21, t(8;21) (q22;q22), is the most frequent abnormality in acute myeloid leukemia (AML) with French-American-British type M2 (FAB-M2) morphology. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO on chromosome 8. The rearrangement of the two chromosomes results in a fusion gene and in the production of a consistent fusion transcript on the der(8) chromosome. We have used oligonucleotide primers derived from both sides of the fusion cDNA junction and reverse transcription-polymerase chain reaction (RT-PCR) to analyze six AML-M2 patients with a t(8;21) during various stages of their disease. Two patients studied at diagnosis and one studied at first relapse are alive off therapy and in continuous complete remission for 83 to 94 months. We have detected the AML/ETO fusion transcript in recent peripheral blood samples from each of them. Three other patients also had a fusion transcript detected after 1 to 4 months in remission. Two of these patients subsequently relapsed and died whereas the third patient is alive and in continuous complete remission 70 months later. Thus, our preliminary data suggest that cells with the translocation are still circulating in t(8;21) patients in long-term remission. This finding raises serious questions regarding the interpretation of positive results obtained only with this technique that may not be suitable to decide appropriate further treatment for patients in clinical remission.

Heterogeneous Chromosomal Mechanisms Generating the 5′RUNX1/3′CBFA2T1 Gene in Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4272-4272
Author(s):  
Giorgina Specchia ◽  
Francesco Albano ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Arcangelo Liso ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
Derivative Chromosome ◽  
Molecular Cytogenetic ◽  
Karyotypic Abnormality ◽  
Fusion Signal ◽  
Acute Myeloid

Abstract Translocation t(8;21)(q22;q22) is a common karyotypic abnormality detected in about 15% of Acute Myeloid Leukemia (AML) cases. The rearrangement results in fusion of the RUNX1 (also known as AML1) and CBFA2T1 (also known as ETO) genes generating a 5′RUNX1/3′CBFA2T1 transcriptionally active fusion gene on derivative chromosome 8. In 1 to 8.5% of AML cases insertions events generating a 5′RUNX1/3′CBFA2T1 fusion gene have been reported, whereas the occurrence of inversions accompanying the t(8;21) has never been observed. We report a screening of 82 AML cases bearing the RUNX1/CBFA2T1 rearrangement detected by RT-PCR; all cases were tested by Fluorescence In Situ Hybridization (FISH) with BAC and PAC clones specific for CBFA2T1 and RUNX1 genes. This analysis allowed us to reveal five cases with ins(21;8), one with ins(8;21), and two with a pericentric chromosome 8 inversion followed by a t(8;21) translocation. A detailed molecular cytogenetic characterization of breakpoints has been performed in all cases. FISH co-hybridization experiments with CBFA2T1 and RUNX1 probes revealed the presence of a functional fusion gene on the der(21) instead of the der(8) chromosome in five cases with ins(21;8); a single fusion signal on the der(8) chromosome was detected in the case with ins(8;21). The use of the same clones in FISH studies showed the presence of a single unexpected fusion signal on the 8p derivative chromosome in addition to faint CBFA2T1 and RUNX1 signals on the long arm of der(8) and der(21) chromosomes, respectively. These results suggested that a pericentric chromosome 8 inversion involving CBFA2T1 gene occurred and that the chromosome 21 was rearranged with the 8p derivative chromosome. Appropriate chromosome 21 and 8 BAC clones were employed to precisely define the size of inserted regions in cases with insertions and the breakpoint on the 8p derivative chromosome in cases showing pericentric chromosome 8 inversion. The insertion size turned out to be very heterogeneous, ranging from a minimum of 2.4 Mb to a maximum of 44 Mb. In both cases with chromosome 8 inversion, the CBFA2T1 gene represents the breakpoint at the chromosome 8 long arm whereas the 8p breakpoint showed different mapping positions in 8p21.3 and 8p21.1, respectively. Our results illustrate that (1) heterogeneous mechanisms can lead to the generation of the 5′RUNX1/3′CBFA2T1 chimeric gene; (2) molecular cytogenetic techniques may identify cryptic chromosomal changes, not detected by conventional cytogenetic analysis; (3) the crucial role of the 5′RUNX1/3′CBFA2T1 fusion gene in leukemogenesis does not depend on its location.

scholarly journals Translocation breakpoints are clustered on both chromosome 8 and chromosome 21 in the t(8;21) of acute myeloid leukemia

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 592-596 ◽  
Author(s):  
JE Tighe ◽  
A Daga ◽  
F Calabi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
Novel Gene ◽  
Translocation Breakpoints ◽  
Acute Myeloid

Abstract The t(8;21)(q22;q22) is consistently associated with acute myeloid leukemia (AML) M2. Recent data have suggested that breakpoints on chromosome 21 are clustered within a single intron of a novel gene, AML1, just downstream of a region of homology to the runt gene of D melanogaster. In this report, we confirm rearrangement at the same location in at least 12 of 18 patients with t(8;21). Furthermore, we have isolated recombinant clones spanning the breakpoint regions on both the der(8) and the der(21) from one patient. By using a chromosome 8 probe derived from these clones, we show that t(8;21) breakpoints are also clustered on chromosome 8.

scholarly journals Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3294-3301 ◽  
Author(s):  
Mark Levis ◽  
Farhad Ravandi ◽  
Eunice S. Wang ◽  
Maria R. Baer ◽  
Alexander Perl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Platelet Recovery ◽  
First Relapse ◽  
Acute Myeloid

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

RUNX1/AML1 DNA Binding Domain and ETO/MTG8 NHR2 Dimerization Domain Are Critical to AML1−ETO9a Leukemogenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 772-772
Author(s):  
Ming Yan ◽  
Scott Hiebert ◽  
Dong-Er Zhang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dna Binding ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Binding Domain ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
Dna Binding Domain ◽  
Dimerization Domain ◽  
Acute Myeloid

Abstract The 8;21 translocation, which involves the gene encoding the RUNX family DNA binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1−ETO fusion proteins. Previous analyses have demonstrated that full length AML1−ETO blocks AML1 function and requires additional mutagenic events to promote leukemia in mice. More recently, we have identified an alternatively spliced form of AML1−ETO, AML1−ETO9a, from t(8;21) AML patient samples (Yan et al. Nat. Med.12:945–949, 2006). AML1−ETO9a lacks the C−terminal NHR3 and NHR4 domains of AML1−ETO and is highly leukemogenic in mice. Here, we report that the AML1 DNA binding domain and the ETO NHR2 dimerization domain, but not the ETO NHR1 domain are critical for the induction of acute myeloid leukemia by AML1−ETO9a. Using retroviral mediated gene expression and hematopoietic cell transplantation in recipient mice, we examined AML1−ETO9a, AML1−ETO9a without the NHR1 domain [AML1−ETO9a (dNHR1)] or the NHR2 domain [AML1−ETO9a(dNHR2)], without a histone deacetylase/Sin3A interacting domain between NHR1 and NHR2 [AML1−ETO9a(d350–428)], and mutant AML1−ETO9a proteins that have lost the capacity to bind DNA [AML1−ETO9a(L148D)] and [AML1−ETO9a(R173Q)] in leukemogenesis. All of the mice transplanted with AML1−ETO9a (n =11) and AML1−ETO9a(dNHR1) (n = 12) expressing cells developed acute myeloid leukemia with a similar phenotype (Lin−/c−kit+) within 21 weeks. The median survival times of mice with AML1−ETO9a and AML1−ETO9a(dNHR1) are 9.4 weeks and 10.5 weeks, respectively. Furthermore, all of the mice expressing AML1−ETO9a(d350–428) (n = 11) also developed leukemia with a median survival time of 17.2 weeks. Significant numbers of AML1−ETO9a(d350–428) expressing cells are positive for myeloid markers CD11b and Gr1 in these leukemic mice. In contrast, none of the mice with AML1−ETO9a(dNHR2) (n = 14), AML1−ETO9a(L148D) (n = 8), and AML1−ETO9a(R173Q) (n = 8) expressing hematopoietic cells developed leukemia. Taken together, these data suggest that the AML1 DNA binding domain and the ETO NHR2 domain are required for AML1−ETO9a induced leukemia development and the region between amino acids 350 and 428 of AML1−ETO9a also affects the differentiation stage and latency of leukemogenesis.

Practically All Patients with Acute Myeloid Leukemia (AML) in Continuous Complete Remission for 3 Years or More Are Cured of Their Disease: The ECOG Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 132-132
Author(s):  
Justin M Watts ◽  
Lynette Zickl ◽  
Mark R Litzow ◽  
Selina M Luger ◽  
Hillard M Lazarus ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Late Relapse ◽  
Published Data ◽  
High Dose ◽  
Acute Myeloid

Abstract Abstract 132 Late relapse in acute myeloid leukemia (AML) has been infrequently studied and variably defined in the literature. Two series have shown that late relapse of AML ≥5 years after first complete remission (CR1) is uncommon, with rates of 1.19–3% (Medeiros et al, Leuk Lymphoma 2007; Verma et al, Leuk Lymphoma 2010). We searched the long-term data available on 784 adults (<60 years-old) who were treated on 1 of 4 ECOG clinical trials (E3483, PC486, E3489, or E1900) and achieved CR1 for reports of late relapse (defined as recurrence of AML ≥3 years after CR1). Median follow-up for the 553 patients last known alive was 11.1 years. The longest median follow-up was 17.2 years on trial PC486. Outcomes We found that 11 patients (1.4%) relapsed late; of these, 2 were treated on E3483, 1 on PC486, 5 on E3489, and 3 on E1900. Seven patients with late relapse died from their disease and 4 were living at last known follow-up. Only 1 patient (0.13%) had recurrence of AML ≥5 years after achieving CR1. It is possible that more late relapses will occur on E1900 (a more recent study with ongoing follow-up). All of these trials except E3483 treated some patients with autologous hematopoietic cell transplantation (autoHCT) as part of post remission therapy. On PC486, no post remission consolidation chemotherapy was administered before autoHCT. Ninety-eight total patients on E3489 and PC486 received autoHCT, and there were no late relapses; on E1900, 2 of the 141 patients treated with autoHCT developed late relapse. No patients who underwent allogeneic (allo) HCT in CR1 experienced late relapse on any of the 4 clinical trials. Nine of the 11 patients with late relapse did not undergo HCT; of these, 5 were consolidated with high-dose cytarabine, 2 received maintenance with low-dose cytarabine and 6-thioguanine, and 2 received unknown post remission therapy. Of the 3 patients with late relapse on E1900, 2 received standard-dose and 1 high-dose daunorubicin with induction. Conclusions Across all 4 trials, only 2 of the 239 patients (0.8%) treated with post remission autoHCT experienced late relapse of AML (≥3 years after CR1), which reinforces previously published data that late relapse after autoHCT is uncommon (Cassileth et al, J Clin Oncol 1993). Furthermore, of the 35 patients treated with autoHCT on PC486, 11 relapsed early and no patients relapsed late, suggesting that post remission chemotherapy may not be necessary before autoHCT. Based on this large AML cohort of nearly 800 patients with long-term follow-up, patients who remain in CCR for at least 3 years have a very low risk of relapse and can be considered cured of their disease. Moreover, given that recurrent AML was extremely rare after 5 years or more of CCR (<0.2%), the risk of therapy-related AML from contemporary induction and post remission strategies including HCT appears to be minimal. Disclosures: No relevant conflicts of interest to declare.

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)

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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