BCOR gene alterations in hematologic diseases

Abstract

The BCL6 corepressor (BCOR) is a transcription factor involved in the control of embryogenesis, mesenchymal stem cells function, hematopoiesis, and lymphoid development. Recurrent somatic clonal mutations of the BCOR gene and its homolog BCORL1 have been detected in several hematologic malignancies and aplastic anemia. They are scattered across the whole gene length and mostly represent frameshifts (deletions, insertions), nonsense, and missence mutations. These disruptive events lead to the loss of full-length BCOR protein and to the lack or low expression of a truncated form of the protein, both consistent with the tumor suppressor role of BCOR.BCOR and BCORL1 mutations are similar to those causing 2 rare X-linked diseases: oculofaciocardiodental (OFCD) and Shukla-Vernon syndromes, respectively. Here, we focus on the structure and function of normal BCOR and BCORL1 in normal hematopoietic and lymphoid tissues and review the frequency and clinical significance of the mutations of these genes in malignant and nonmalignant hematologic diseases. Moreover, we discuss the importance of mouse models to better understand the role of Bcor loss, alone and combined with alterations of other genes (eg, Dnmt3a and Tet2), in promoting hematologic malignancies and in providing a useful platform for the development of new targeted therapies.

Graphical abstract

Figure 1.

BCOR and BCORL1 proteins. (A) The BCOR protein is characterized by the BCL6 binding site, the AF9 (MLLT3) binding site, the ANK repeats, and the PUFD binding site capable to dimerize with PCGF1. When the BCOR PUFD domain binds to the RAWUL domain of PCGF1, the complex acquires stability and therefore BCOR is able to interact with the leucine-rich repeat domains of KDM2B. Other components of the multiprotein complex include the catalytic enzyme RING1A/B, RYPB, and SKP1. (B) The BCORL1 protein is characterized by the CtBP1 binding site (CBS), 2 LXXLL (nuclear receptor recruitment motifs), the ANK repeats, and the PUFD binding site.

Figure 2.

Noncanonical PRC1.1 complex and canonical PRC2 and PCR1 complexes in HSCs. The BCOR complex is recruited to the chromatin via binding of KDM2B to nonmethylated CpG islands, and it catalyzes the ubiquitination of the histone H2A at Lys119 (H2AK119ub) via the RING-PCGF1 enzymatic core. Ubiquinated loci (white asterisk) recruit the histone methyltransferase EZH2, one of the components of the polycomb repressor complex 2 (PRC2). PRC2 is then responsible for the histone H3 methylation at Lys27 (H3K27me3). All these histone modifications lead to the suppression of gene transcription. Canonical PRC1 complex through its components RING1B and CBX catalyzes both the ubiquitination of the histone H2A at Lys119 (H2AK119ub) and the histone H3 methylation at Lys27 (H3K27me3), also leading to the suppression of gene transcription.

Figure 3.

Role of BCOR and noncanonical PRC1.1 complex in the germinal centers of B-cell follicles. Mantle naïve B cells do not express BCL6. Germinal center B cells strongly express BCL6 (nuclear brown positivity at immunoperoxidase staining with monoclonal antibody PG-B6p⁴²). BCL6 interacts with BCOR to recruits the PRC1.1 that leads to the epigenetic transcriptional repression of BCL6 target genes. CBX8 is also a component of the complex in the germinal center B cells. The white asterisk indicates recruitment of PRC2 to the ubiquitinated loci. In addition to BCOR, the POZ domain of BCL6 also interacts with the SMRT and N-CoR corepressors that are part of the large multiprotein histone deacetylase-containing complexes and are also required for the repressive activity of BCL6. These events result into the temporary silencing of genes controlling differentiation of B cells to plasma cells and cell cycle checkpoint (CDKN1A, CDKN1B) to allow immunoglobulin affinity maturation. B cells that exit from germinal center downregulate BCL6 before giving raise to plasma cells and memory B cells.

Figure 4.

BCOR and BCORL1 mutations in hematologic malignancies. (A,C) The numbers indicate the coding exon, whereas the plots indicate the mutations in BCOR (A) and BCORL1 (C). Red plot = nonsense mutation; orange plot = silent in frame insertion; green plot = missense mutation; black plot = frameshift mutation (deletion + insertion); pink plot = unknown mutation. (B,D) Frequency of mutations for each BCOR (B) or BCORL1 (D) exon detected on myeloid neoplasms, lymphoid neoplasms, and in both of them.

Figure 5.

BCOR functional loss cooperates with other mutations to promote AML. Disruptive BCOR mutations that cause loss of the native protein or generate a truncated protein abrogate the capability of BCOR to bind PCGF1, thus preventing its interaction with KDM2B and the formation and recruitment to chromating of the enzymatic core. Thus, in hematopoietic stem and progenitor cells (HSPCs), the repressive activity of the complex is abrogated resulting into the expression of Hox and Cebp family genes. The occurrence of additional mutations (eg, DNMT3A and RUNX1) promotes the development of AML. Whether BCOR mutations precede or follow DNMT3A and RUNX1 mutations remains to be established.

Figure 6.

Schematic representation of BCOR knockout and double compound mouse models. The presence of different partner mutations in the Bcor conditional knockout mouse model (Bcor^Δ4/Y, Bcor^Δ9-10/Y, Bcor^Δ8-10/Y) variably affects the severity and penetrance of the disease phenotype. In particular, Bcor^Δ4/Y,p53^−/− mice exacerbate the T-ALL developed in Bcor^Δ4/Y mice. Compound mutant mice carrying Bcor^Δ9-10/Y,Tet2^−/− mutations develop a progressive lethal MDS. Compound mice comutated for Bcor^Δ9-10/Y, and Kras^G12D develop AML, and mice comutated for Bcor^Δ8-10/Y and Dnmt3a^Δ19-20 develop acute erythroid leukemia (AEL). An approach of multiplex genome editing of primary mouse hematopoietic stem and progenitor cell transplanted in a clustered regularly interspaced short palindromic repeat (CRISPR)-cas9 mice compound demonstrates that comutations of Bcor, Trp53 plus Dnmt3a or Rb1 or Nfix results in AEL. In contrast, the contemporary comutations of Bcor, Dnmt3a, Trp53, and tet2 result in T-ALL, and the contemporary comutations of Bcor, tet2 and Sf3b3 lead to B-ALL.