Abstract
Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a heterogeneous malignant clonal disorder arising from multipotent hematopoietic progenitor cells characterized by genetic and concerted epigenetic aberrations. Core binding factor-Leukemia (CBFL) is characterized by the recurrent reciprocal translocations t(8;21)(q22;q22) or inv(16)(p13;q22) that, expressing the distinctive RUNX1-RUNX1T1 (also known as Acute myeloid leukemia1-eight twenty-one, AML1-ETO or RUNX1/ETO) or CBFB-MYH11 (also known as CBFβ-SMMHC) translocation product respectively, disrupt the essential hematopoietic function of the CBF. In the past decade, remarkable progress has been achieved in understanding the structure, three-dimensional (3D) chromosomal topology, and disease-inducing genetic and epigenetic abnormalities of the fusion proteins that arise from disruption of the CBF subunit alpha and beta genes. Although CBFLs have a relatively good prognosis compared to other leukemia subtypes, 40–50% of patients still relapse, requiring intensive chemotherapy and allogenic hematopoietic cell transplantation (alloHCT). To provide a rationale for the CBFL-associated altered hematopoietic development, in this review, we summarize the current understanding on the various molecular mechanisms, including dysregulation of Wnt/β-catenin signaling as an early event that triggers the translocations, playing a pivotal role in the pathophysiology of CBFL. Translation of these findings into the clinical setting is just beginning by improvement in risk stratification, MRD assessment, and development of targeted therapies.
Highlights
The year 2016 coincided with the 25th anniversary of the first cloning of mammalian Runt (Runt domain)-related transcription factor 1 (RUNX1) gene, associated with hematologic disorders [1].RUNX1 (AML1) is a master transcriptional regulator of adult hematopoiesis involved in the establishment, maintenance, and functional integrity of hematopoietic stem cells (HSCs) in embryonic and adult blood compartments [2,3,4]
The authors found that in vivo treatment with the HDAC1 inhibitor induced differentiation and apoptosis of leukemia cells, indicating HDAC1 as a potential therapeutic target [59]. These findings suggest an important role for core binding factor-β (CBFβ)-SMMHC in regulating the expression of genes essential for emergence of the hematopoietic stem cell [60]
Genetic definition of Core binding factor-Leukemia (CBFL) patients using deep sequencing approaches illustrate that we are only beginning to understand how fusion proteins involving the core binding factor (CBF) are integrated into the molecular networks of transcriptional and epigenetic regulators
Summary
The year 2016 coincided with the 25th anniversary of the first cloning of mammalian Runt (Runt domain)-related transcription factor 1 (RUNX1) gene, associated with hematologic disorders [1]. The hypothesis that Wnt signaling promotes genomic proximity between RUNX1 and RUNX1T1 has been recently examined by experiments establishing that Wnt/β-catenin signaling supports RUNX1 and RUNX1T1 expression in hematopoietic precursors and provides spatial information, indicating that transcription of these genes is likely occurring into RNA-polymerase-II nuclear factories (RNAPII-Ser5) [10] Several studies documented the multifunctionality of AML1-ETO fusion protein, including impaired differentiation, apoptosis inhibition, and signal activation for cell proliferation This model might be oversimplified; there is convincing evidence supporting the hypothesis that leukemias are induced by cooperation between alterations in protein-coding genes and microRNAs (miRNAs), an entire novel epigenetic targets linked to leukemia development [22].
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