Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome

Abstract

<i>BCOR</i>, 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 <i>Bcor</i> exon 4 (<i>Bcor</i> ^{<i>ΔE4/y</i>} ) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking <i>Bcor</i> exons 9 and 10 (<i>Bcor</i> ^{<i>ΔE9-10/y</i>} ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. <i>Bcor</i> ^{<i>ΔE9-10/y</i>} mice developed lethal T-ALL in a similar manner to <i>Bcor</i> ^{<i>ΔE4/y</i>} mice, whereas <i>Bcor</i> ^{<i>ΔE9-10/y</i>} hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of <i>Tet2</i> <i>Tet2</i> ^<i>Δ/Δ</i> <i>Bcor</i> ^{<i>ΔE9-10/y</i>} mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. <i>Tet2</i> ^<i>Δ/Δ</i> <i>Bcor</i> ^{<i>ΔE9-10/y</i>} 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 <i>Cebp</i> family and <i>Hoxa</i> cluster genes in <i>Bcor</i> ^{<i>ΔE9-10/y</i>} 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 <i>Bcor</i> insufficiency on the initiation and progression of MDS.