Disease Features in Acute Myeloid Leukemia with t(8;21)(q22;q22). Influence of Age, Secondary Karyotype Abnormalities, CD19 Status, and Extramedullar Leukemia on Survival

Rege, Kanchan; Swansbury, G. J.; Atra, Ayad; Horton, C; Min, Toon; Dainton, Melissa; Matutes, E.; Durosinmi, M. A.; Treleaven, J; Powles, R; Catovsky, Daniel

doi:10.3109/10428190009054882

Cited by 69 publications

(48 citation statements)

References 18 publications

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“…Notably, the loss of a sex chromosome and deletion of chromosome 9q are most common and their impact on survival is controversial. 1,5,15,[17][18][19][20] In this study, we confirmed that the loss of a sex chromosome and del(9q) were common, in 22 (39%) and six (11%) cases, respectively, and these aberrations did not correlate with poorer clinical outcome. These results are in keeping with the observations by other investigators who had 4100 cases in their respective study series.…”

Section: Discussionsupporting

confidence: 72%

“…The strength of our series is that the large majority of newly diagnosed patients were treated similarly in a single institution instead of multiple different protocols as in earlier large series, allowing us to assess the prognostic factors across different subgroups despite the relatively small cohort size. The del(9q) was identified as a negative 16 or positive 18 prognostic factor in one study each. In the former study, 7 of 50 patients with del(9q) had a median OS of 12.5 months.…”

Section: Discussionmentioning

confidence: 92%

“…16 In the latter, 8 of 51 patients with an abnormal long arm of chromosome 9 (two with translocations and six with partial deletions) had a longer event-free survival of unspecified time. 18 These two studies highlight the limitation of small study series and difficulty comparing data from various study series.…”

Section: Discussionmentioning

confidence: 99%

“…This is particularly true regarding implications of additional cytogenetic aberrations. Loss of a sex chromosome and del(9q) have been reported to adversely, 16 favorably 1,17,18 or marginally affect the survival of patients with t(8;21). 5,15,19,20 Earlier studies were largely based on the observation of patients treated with conventional chemotherapy regimens with idarubicin and cytarabine (ara-C).…”

mentioning

confidence: 99%

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Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Lin¹,

Chen

Luthra³

et al. 2008

Modern Pathology

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Acute myeloid leukemia with t(8;21)(q22;q22) is a distinct type of leukemia considered to have a favorable prognosis. However, some patients rapidly succumb to disease despite chemotherapy. We studied 56 patients with acute myeloid leukemia associated with t(8;21) and correlated clinicopathologic, cytogenetic and molecular findings with outcome to identify markers of prognosis. In a subset of patients, we also assessed the status of the c-KIT, FLT3 and RAS genes. There were 31 men and 25 women, with a median age of 38 years (range 4-76). The follow-up period ranged from 17 to 104 months (median 52). At the last follow-up, 29 patients had died, 25 patients were in complete remission and two patients were alive with disease. The median survial was 38 months. The 5-year overall survival rate of newly diagnosed patients was 56%. Most patients (39/56, 70%) had chromosomal aberrations in addition to t(8;21), with loss of a sex chromosome (39%) being most common followed by del(9q)(q21-22) (11%) and trisomy 8 (7%). These aberrations, however, did not predict survival. C-KIT (D816V or D816Y), FLT3 (ITD or D835) and RAS mutations were detected in 26, 10 and 7%, respectively, of cases assessed. The 5-year overall survival rate of patients with mutated leukemia was 20%. No mutations were observed in three patients who died within 7 months of diagnosis. Leukocytosis or CD56 expression did not correlate with a poor survival nor did the levels of CD19 expression predict c-KIT mutation status. We conclude that acute myeloid leukemia associated with t(8;21) is a heterogeneous disease with poor survival in a subset of patients unrelated to common secondary cytogenetic aberrations. Keywords: t(8;21); cytogenetics; c-KIT mutation The t(8;21)(q22;q22) is the most common cytogenetic abnormality in acute myeloid leukemia (AML), occurring in up to 12% of patients. 1 As a result of t(8;21), the ETO (MTG8) gene on chromosome 8 is fused to the AML1 (RUNX1) gene on chromosome 21, producing a novel chimeric gene, AML1-ETO. The AML1 gene encodes the alpha subunit of core-binding factor (CBF) that is essential for normal hematopoiesis. AML1-ETO fusion gene disrupts the CBF transcription complex, thus initiating the first step of leukemogenesis. 2 The AML1-ETO fusion protein is a multifunctional cellular protein that affects cell differentiation, proliferation, apoptosis and self-renewal. 3 Evidence suggests that additional cytogenetic aberrations may act synergistically with AML-ETO in leukemogenesis. 3 AML with t(8;21), similar to AML with inv(16) or t(15;17), is generally considered a disease with an overall favorable prognosis characterized by a higher response rate and longer median survival compared with other types of AML. This concept is adopted in the current World Health Organization Classification. 4 Of the two references cited by the WHO classification, both published in 1998, 5,6 one was a British study of 1612 AML patients in which 122 patients had AML with t(8;21). The 5-year overall survival (OS) rate of patients with t(8;21) ...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Lin¹,

Chen

Luthra³

et al. 2008

Modern Pathology

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“…AML1-ETO is a fusion protein transcription factor generated from t(8;21)(q22;q22). This translocation is identified in Ͼ10% of all cases and up to 40% of the French-American-British M2 subtype of AML (2)(3)(4)(5). However, expression of AML1-ETO by itself fails to cause leukemia (6)(7)(8)(9)(10)(11), which suggests the requirement of ''additional hits'' for AML1-ETO-positive cells to become leukemogenic.…”

mentioning

confidence: 99%

Disruption of the NHR4 domain structure in AML1-ETO abrogates SON binding and promotes leukemogenesis

Ahn

Yan

Malakhova

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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AML1-ETO is generated from t(8;21)(q22;q22), which is a common form of chromosomal translocation associated with development of acute myeloid leukemia (AML). Although full-length AML1-ETO alone fails to promote leukemia because of its detrimental effects on cell proliferation, an alternatively spliced isoform, AML1-ETO9a, without its C-terminal NHR3/NHR4 domains, strongly induces leukemia. However, full-length AML1-ETO is a major form of fusion product in many t(8;21) AML patients, suggesting additional molecular mechanisms of t(8;21)-related leukemogenesis. Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, demonstrating that the NHR4 domain with the intact structure generates inhibitory effects on leukemogenesis. C hromosomal translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML) (1). AML1-ETO is a fusion protein transcription factor generated from t(8;21)(q22;q22). This translocation is identified in Ͼ10% of all cases and up to 40% of the French-American-British M2 subtype of AML (2-5). However, expression of AML1-ETO by itself fails to cause leukemia (6-11), which suggests the requirement of ''additional hits'' for AML1-ETO-positive cells to become leukemogenic.Previously, our group reported that the C-terminally truncated form of AML1-ETO (AML1-ETOtr) is strongly leukemogenic (12). Interestingly, a short form of AML1-ETO, AML1-ETO9a, which is produced by alternative splicing, was identified in t(8;21) leukemia patient samples, and expression of AML1-ETO9a induced rapid leukemia development in mice (13). AML1-ETOtr and AML1-ETO9a encode 556 and 575 aa (a.a.), respectively, and both lack the NHR3 and NHR4 regions. These results suggest that the N-terminal portion of ETO (NHR1 and NHR2) fused with AML1, is sufficient to cause leukemia. In addition, the C-terminal domains of AML1-ETO (NHR3 and NHR4) may actually play a role in suppressing disease development.In this report, we demonstrate that the zinc (Zn)-chelating structure of the NHR4 is responsible for generating inhibitory effects on leukemia development, and that this region interacts with SON, a potential DNA/RNA-binding protein, to cause growth arrest in AML1-ETO-expressing cells. Furthermore, we demonstrate a crucial role of SON in cell proliferation, and abnormal localization of SON in AML1-ETO-expressing leukemia patient samples.

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Acute Myeloid Leukaemia

2017

Leukaemia Diagnosis

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Disease Features in Acute Myeloid Leukemia with t(8;21)(q22;q22). Influence of Age, Secondary Karyotype Abnormalities, CD19 Status, and Extramedullar Leukemia on Survival

Cited by 69 publications

References 18 publications

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Disruption of the NHR4 domain structure in AML1-ETO abrogates SON binding and promotes leukemogenesis

Acute Myeloid Leukaemia

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