Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

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.

Defining the transcriptional control of pediatric AML highlights RARA as a superenhancer-regulated druggable dependency

“…Although the 2 CBF-rearranged AML samples [t(8;21) and inv(16)] did not cluster together by SE similarity ( Figure 1B ), both contained a RARA SE. This finding suggests that transcriptional regulation could contribute to the biologic differences in this heterogeneous subtype of CBF AML 27 ; however, more samples of each CBF subtype are needed to determine the true frequency of a RARA SE. The sample with the lowest ranked RARA SE, p151 ( Figure 1F ), was from a patient with trisomy 21 who presented with transient myeloproliferative disorder, a potentially self-resolving condition.…”

Comprehensive Analysis of HDAC Family Identifies HDAC1 as a Prognostic and Immune Infiltration Indicator and HDAC1-Related Signature for Prognosis in Glioma

“…Retinoblastoma transcriptional corepressor like 1 (RBL1), known for its modulation in the G1/S cell cycle, behaved oppositely and functioned as a tumor suppressor in a GBM model, conflicts of which could come from either the species’ differences or some other regulations unidentified ( Naert et al, 2020 ). RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) earned prestige for its fusion with Runt-related transcription factor 1 (RUNX1) in acute myeloid leukemia ( Beghini, 2019 ). Related to HDAC class I signaling, FK506 Binding Protein 3 (FKBP3) regulated HDAC2 expression contributing to the drug resistance in tumor cells ( Tong et al, 2019 ).…”

Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

“…RUNX1-RUNX1T1 (AML1-ETO) recruits a multitude of co-repressors to its binding sites, whereas somatic mutations of RUNX1 , which often target sequences coding for the Runt Homology Domain, are inactivating or confer dominant-negative activity ( Sood et al.,2017 ). Functionally, RUNX1 may be sequestered away from chromatin by CBFB-SMMHC or have its activity modified by interaction with CBFB-SMMHC, which also recruits co-repressors to sites of RUNX1 binding ( Beghini, 2019 ). Biallelic mutations in CEBPA , which block CEBP factor homo- or heterodimerization, or DNA binding, are also frequent in AML ( Wilhelmson and Porse, 2020 ).…”