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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Cytogenetic abnormalities used in the WHO classification (Vardiman et al., 2009) are shown in Table 10.1. Approximately 10% of adult AML and 20% of childhood AML are classified as having core binding factor (CBF) leukemia with balanced chromosomal rearrangements that disrupt gene RUNX1 (also known as CBFA2 or AML1), which plays a critical role in hematopoiesis and leukemogenesis (Lam and Zhang, 2012; Marcucci, 2006; Metzeler and Bloomfield, 2017; Mrózek et al., 2008; Sangle and Perkins, 2011; Utsun and Marcucci, 2015; Yamagata et al., 2005). Patients with two specific, clonal, recurring cytogenetic abnormalities t(8;21)(q22;q22), inv(16)(p13.1q22) or t(16;16)(p13.1q22) are called CBF AML. Compared to other cytogenetic AML subgroups, CBF AML is considered a more favorable subset of AML (Table 10.2). CBF AML results in the formation of hybrid fusion genes called RUNX1-RUNX1T1 (also known as AML1-ETO) and CBFB-MYH11, which can be quantified in patients before, during, and after the therapy, including stem cell transplantation (Yin et al., 2012). Favorable karyotype patients have a good prognosis with complete remission rates exceeding 90%, a five-year survival of at least 65%, and relapse rates too low and salvage rates too high to benefit from routine use of allograft in first complete remission (Smith et al., 2011).
Cytogenetics
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The t(8;21)(q22;q22.3) translocation is seen in AML and is characteristically associated with AML with maturation subtype and frequent coexpression of CD34, CD19, and CD56 [36,199–202]. This translocation is one of the most frequent structural chromosomal abnormalities seen in AML and are reported in 6%–20% of AML cases. The t(8;21) results in fusion between RUNX1 (Runt-related gene family; formerly termed AML1 gene) and RUNX1T1 genes (formerly ETO for eight twenty-one), producing a chimeric protein, RUNX1–RUNX1T1 [203]. AML with t(8;21) belongs to a group of CBF leukemias. CBF is also rearranged in AML with t(3;21) and t(16;16)/inv(16). AML with t(8;21) is found more frequently in children and young adults and displays predisposition for extramedullary localization [204,205]. This subtype of AML is associated with a favorable prognosis [12,118,204,205]. Additional cytogenetic abnormalities in AML with t(8;21) are common (75%) and may include −X, −Y, del(9)(q22), +8, and +4 [206,207]. Approximately 28% of patients show more than one chromosomal abnormality [206]. Additional abnormalities did not have a significant adverse effect in t(8;21) AML [12].
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Efforts assessing the genetic and molecular abnormalities in patients with AML have helped define risk category and personalized therapy. Patients can be classified into groups with different prognoses based on cytogenetic and molecular analyses (Figure 28.3).14 For example, leukaemia with an isolated mutation in NPM1 or bi-alleleic CEBPa is associated with a favourable prognosis; those with t(8;12), inv(16) or t(16;16) also appear to have a favourable prognosis, with the best response and remission rates (under age 60 years), except when associated with the kit mutation, when the relapse risk increases with, at least in some reports an adverse impact on survival thus potentially reclassifying them to an intermediate category. It is of interest that these translocations disrupt the core binding factor (CBF) complex, which plays an essential role in normal haematopoiesis. The CBF complex is composed of an alpha and a beta subunit, with the alpha subunit encoded by one of three homologous genes of the Runt-related transcription factor (RUNX) family, whereas CBF beta subunit by the CBFB (also known as PEBP2B) gene which is involved in inv(16)/t(16;16). The RUNX1 gene is involved in three different chromosomal translocations, which share a break-point at its site on chromosome 21q22: t(8;21), t(3;21) and t(12;21); the t(8;21) juxtaposes RUNX1 to RUNX1T1 (previously known as AML1-ETO).15 Patients with a normal karyotype but a mutation in FLT3 (FMS-like tyrosine kinase), a transmembrane tyrosine kinase with either a single amino-acid substitution in the kinase domain, or with an internal tandem duplication (ITD), tend to have an intermediate-risk AML although they may have associated features such as a high presenting white count which increases the risk. It is becoming increasingly clear that the prognostic implications of FLT3 mutations are influenced by the alleleic ration and whether it occurs in association with the more favourable NPM1c mutation. Leukaemia cells with translocations involving the mixed-lineage leukaemia (MLL) gene at 11q23, t(6;9) or complex (greater than 3) abnormalities, monosomies of any chromosome (typically chromosome 5 and/or 7), inv(3), t(3;3), t(6;9), and 17p abnormalities indicate a poor-risk AML.16
Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia
Published in Hematology, 2023
Wenwen Guo, Xin Liu, Mingyang Wang, Jia Liu, Yigeng Cao, Yawei Zheng, Weihua Zhai, Xin Chen, Rongli Zhang, Qiaoling Ma, Donglin Yang, Jialin Wei, Yi He, Aiming Pang, Sizhou Feng, Mingzhe Han, Erlie Jiang
Acute myeloid leukemia (AML) carrying the t(8;21) chromosomal translocation, which corresponds to the RUNX1/RUNX1T1 fusion, is classified as a favorable-risk AML subset. For most t(8;21) AML patients, complete remission (CR) can be achieved because of their high sensitivity to standard induction chemotherapy. Moreover, cytarabine-based consolidation therapy can provide long-term remission. However, up to 40% of patients may still experience relapse [1–3]. Allogeneic hematopoietic cell transplantation (allo-HCT) can improve the prognosis of high-risk t(8;21) AML patients [4, 5]. However, as a disease with heterogeneous characteristics, nearly 15% – 20% of t(8;21) AML patients who undergo allo-HCT experience relapse with a dismal outcome [6–8]. Therefore, it is urgent to identify patients at high risk of relapse and implement strategies to improve their survival.
The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study
Published in Hematology, 2022
Lixia Zhu, Rongrong Chen, Xueying Li, Mixue Xie, Xiudi Yang, Jianai Sun, Mingyu Zhu, Xiaolong Zheng, Li Li, Jingjing Zhu, De Zhou, Wanzhuo Xie, Xiujin Ye
The translocation (8;21) involves the acute myeloid leukemia 1 (AML1) (also call runt-related transcription factor 1(RUNX1)) gene on chromosome 21 and the corepressor eight-twenty-one (ETO) (MTG8, RUNX1T1) gene on chromosome 8 [6], which is more frequently associated with additional cytogenetic abnormalities (ACAs). The most common cytogenetic abnormalities associated with t(8;21) include the loss of sex chromosome (LOS), deletions of the long arm of chromosome 9 (del9q) and complex abnormalities [7]. The LOS is the most common ACA, occurring in t(8;21) AML in a relatively high percentage of cases (32%−66%) [8–10]. Although some studies have reported the clinical significance of the loss of sex chromosome (LOS) in t(8;21) AML, its prognostic value is still a matter of debate. Some studies have suggested that the prognosis of t(8;21) AML with LOS was poor [11,12], while several reports have concluded that deletion of the sex chromosome was a favorable prognostic factor [13,14]. However, few studies have considered the possible negative impact of del (9q) or complex karyotype on prognosis, which has been reported in previous reports [7,15], which may result in conflicting data regarding the prognostic value.
Mutational landscape of patients with acute myeloid leukemia or myelodysplastic syndromes in the context of RUNX1 mutation
Published in Hematology, 2020
Kai Wang, Feng Zhou, Xiaohui Cai, Hongying Chao, Ri Zhang, Suning Chen
The runt-related transcription factor 1 (RUNX1) gene, a member of the transcription factor family, is a critical regulator of myeloid differentiation and involved in hematopoietic stem cell emergence and regulation [1,2]. RUNX1 was first identified as the fusion partner of RUNX1T1 (ETO) in patients with translocation involving t(8;21) acute myeloid leukemia (AML) [3]. Previously reported that rare germline RUNX1 mutations are associated with the autosomal dominant familial platelet disorder (FPD) predisposing the affected individuals to AML [4]. Recently, acquired RUNX1 mutations have been found in 5–10% of de novo AML, showing prognostic adverse impact on overall survival and disease progression [5,6]. Several studies have demonstrated RUNX1 mutations are correlated with distinct clinicopathologic features, and inferior prognosis [5,6]. Based on the accumulated evidence, RUNX1-mutatedAML has been included as a new provisional entity in the revised 2016 World Health Organization (WHO) classification of human myeloid neoplasms [7].