Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts

Abstract

IntroductionAcute myeloid leukemia (AML) is a heterogeneous disease that is classified based on the presence of specific cytogenetic abnormalities as well as the French-American-British (FAB) classification of the leukemic cells and immunophenotype. One of the common translocations identified in leukemia is between chromosome 8q22 and chromosome 21q22 ( Figure 1a). 1 It is associated with nearly 40% of cases of FAB-M2 AML and 8% to 20% of all cases of AML depending on the genetic background and geographic location of the population. The (8;21) translocation is also observed in approximately 6% of AML M1 and, more rarely, in AML M0, M4, M5, and other myeloproliferative syndromes. 2,3 The involved genes are, on chromosome 8, MTG8 or ETO, meaning myeloid translocation gene or eight twenty-one, respectively, 4,5 and AML1 (acute myeloid leukemia factor 1) on chromosome 21. 4 The commonly used name for the t(8;21) fusion protein is AML1-MTG8 or AML1-ETO, and we refer to it as AML1-ETO in this review. AML1 was also discovered from other studies that are not related to t(8;21) and has several different names. 6 Its HUGO (Nomenclature Committee of the Human Genome Organization) name is RUNX1. In correlation, MTG8/ETO is named RUNX1T1 for RUNX1 translocation 1.The t(8;21) generates the 2 fusion genes AML1-ETO and ETO-AML1 ( Figure 1B). AML1-ETO mRNA is easily detectable using polymerase chain reaction (PCR) primers on 2 sides of the fusion point. However, ETO-AML1 mRNA was not identified using a similar approach (E. Kanbe, D.-E.Z., unpublished data, February 2003). This result indicates that the ETO-AML1 transcript is not expressed, is expressed at an extremely low level, or is highly unstable due to degradation. All of the studies on t(8;21) have therefore focused on AML1-ETO.Most of the coding region of the ETO gene is fused to the AML1 amino terminus containing the DNA-binding runt homology domain (RHD) to generate an AML1-ETO fusion protein ( Figure 1C). 4,5,7 The ETO gene has 14 exons. The original cloned AML1-ETO cDNA contained ETO exons 2 through 11; the fusion transcript produces an AML1-ETO protein of 752 amino acids ( Figure 1C). 8 The ETO portion of the full-length AML1-ETO protein contains 3 proline-serine-threonine (PST)-rich regions and 4 Nervy homology regions (NHR1-4) ( Figure 1C). 9 The PST-rich regions have multiple potential kinase phosphorylation sites (SP [Serine-Proline] and TP [Threonine-Proline]). Phosphorylation of ETO has been reported although no kinase involved in its phosphorylation has been identified. 10 NHR1, also called the TAF (TATA box binding protein associated factor) homology domain, shares a sequence similarity with TAF110 and other related TAFs. NHR2 has a hydrophobic amino acid heptad repeat, which is critical for ETO oligomerization. 11 NHR3 contains a predicted coiled-coil structure. NHR4 is a myeloid-Nervy-DEAF1 (MYND) homology domain with 2 predicted zinc finger motifs.Expression of the AML1-ETO fusion gene is under the control of the AML1 promoter. The AML1 gene has 2 promot...

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

“…At least 10 somatically acquired chromosomal translocations involving RUNX1 have been described in AML (Mikhail et al, 2002). Among these, the translocation between chromosome 8q22 and chromosome 21q22, t(8;21), is the most common and is associated with approximately 40% of AML-M2 (French-American-British classification) and 8-20% of all AML cases (Peterson et al, 2007a). The translocation results in the production of a fusion protein that consists of 177 amino acids of RUNX1 containing the Runt domain fused to 575 amino acids of RUNX1T1 (also known as ETO or MTG8).…”

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

“…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.…”

“…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.…”

AML1/ETO and POU4F1 synergy drives B-lymphoid gene expression typical of t(8;21) acute myeloid leukemia

“…4 The POU homeobox gene POU4F1 (also known as BRN3A) is highly expressed in t(8;21) samples, with AML1/ETO appearing both to promote some BRN3A expression and co-operate with its protein product Brn3a to restrict myeloid gene expression. 5,6 An ability of Brn3a shRNA to impair AML1/ETO-dependent immortalisation of murine haematopoietic progenitor cells in vitro suggests an important role for BRN3A in the human disease.…”

“…Detailed analysis of clinical parameters and cytogenetic findings was performed to risk stratify patients according to the Dynamic International Prognostic Scoring System (DIPSS)-plus. 4 All patients were also screened for JAK2, MPL and IDH mutations, using previously described methods. 5 --7 SF3B1-coding exon sequencing was performed using bone marrow-or granulocyte-derived DNA extract (Qiagen, Valencia, CA, USA).…”