Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome

Abstract

<jats:title>Abstract</jats:title> <jats:p>BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (BcorΔE4/y) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (BcorΔE9-10/y), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. BcorΔE9-10/y mice developed lethal T-ALL in a similar manner to BcorΔE4/y mice, whereas BcorΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2. Tet2Δ/ΔBcorΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2Δ/ΔBcorΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in BcorΔE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.</jats:p>

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

“…The type of myeloid neoplasm developing in Bcor-deficient mouse may vary depending on the co-occurring genetic lesions. For example, compound mice carrying concurrent full deletion of Tet2 develop lethal MDS [19] whilst Bcor loss cooperates with Kras G12D to drive AML [17].…”

Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

“…Recently, Tara et al demonstrated that Bcor mutation which lacks interaction with non-canonical PRC1.1 containing PCGF1 and promotes MDS/MPN development in mouse model [71]. This Bcor mutant mouse showed substantial derepression of Hoxa7 and Hoxa9 gene via reduction of H2AK119ub at the Hoxa7 and Hoxa9 gene loci.…”

Deregulated Polycomb functions in myeloproliferative neoplasms

“…The depletion of both Runx1 and Pcgf1 resulted in the maintenance of proliferation of hematopoietic progenitor cells and perturbed their differentiation because of increased expression of posterior Hoxa cluster genes such as Hoxa9 [21]. Similarly, myeloid cells in mice lacking Bcor exons 9 and 10, which generates a truncated form of Bcor that does not bind Pcgf1, have a higher proliferative capacity, which results in myeloid-biased hematopoiesis [22,23]. Bcor-deficient HSCs have increased expression of Cebp family genes in MPPs and sustained expression of posterior Hoxa cluster genes in myeloid progenitors [23].…”

“…Similarly, myeloid cells in mice lacking Bcor exons 9 and 10, which generates a truncated form of Bcor that does not bind Pcgf1, have a higher proliferative capacity, which results in myeloid-biased hematopoiesis [22,23]. Bcor-deficient HSCs have increased expression of Cebp family genes in MPPs and sustained expression of posterior Hoxa cluster genes in myeloid progenitors [23]. These findings indicate that PCR1.1 negatively regulates critical transcriptional regulator genes, such as Cebp, and Hoxa9, to restrict the proliferation and differentiation of myeloid progenitor cells.…”

“…Bcor ∆E9−10/y mice in combination with a Tet2 hypomorph develop lethal MDS, which transforms into MDS/MPN after a secondary transplantation. Bcor ∆E9−10/y multipotent and myeloid progenitors have enhanced expression of Cebp family genes and posterior Hoxa cluster genes, respectively, because of reductions in H2AK119ub1 levels at the promoters of myeloid-regulator genes [23]. In addition, deletion of Kdm2b accelerates oncogenic KRAS-mediated myeloid transformation, and ectopic expression of Kdm2b suppresses the progression of KRAS-induced myeloid malignancies [74].…”