Epigenetic plasticity in human acute myeloid leukemia pathogenesis

What is it about?

Transcriptional plasticity is an evolving phenomenon in cancer biology. Tumor cell type-specific transcriptional dependencies cannot be addressed only using genome sequencing studies. Acute myeloid leukemia (AML) is the second most common leukemia worldwide with a median age of ~ 65 years at diagnosis. Despite progress in our understanding of AML pathogenesis the overall 5-year survival is ~ 20% due to low remission and high incidence of relapse. In the present study we took focused mechanistic approach towards understanding gene control programs operating within human primary leukemia cells in order to identify novel epigenetic vulnerability. Rac GTPases critically regulate leukemia cell survival, however the precise regulation of Rac activity in AML is incompletely understood. Nucleosome remodeling and deacetylase (NuRD) is an ATP-dependent chromatin remodeling complex that critically regulates cell-fate commitment and transcriptional architecture of murine embryonic stem cells. We investigated contribution of NuRD complex in human AML pathobiology. We identify that loss of MBD3, an important scaffold of NuRD complex, in primary AML cells associates with leukemic NuRD, which retains CHD4 ATPase subunit. Interestingly, CHD4 interacts and participates with H3K27-demethylase KDM6A to regulate Rac GTPase guanine-nucleotide-exchange-factors GEFs (DOCK5/8) expression and Rac activation in AML cells. Analysis of TCGA AML dataset suggests that DOCK5/8 expression is significantly increased in MBD3loKDM6Ahi patients with a relatively poor survival compared to MBD3hiKDM6Alo AML, and pharmacological inhibition of DOCK signaling selectively attenuates AML cell survival. Together our results illustrate a hitherto unidentified epistasis between NuRD and KDM6A towards maintenance of oncogenic gene expression in AML.

Featured Image

Why is it important?

Tumor cell type-specific transcriptional dependencies cannot be addressed only using genome sequencing studies. In the present study we took focused mechanistic approach towards understanding gene control programs operating within human primary leukemia cells in order to identify novel epigenetic vulnerability. Rac GTPases critically regulate leukemia cell survival, however the precise regulation of Rac activity in AML is incompletely understood. We identify that loss of MBD3 in primary AML cells associates with leukemic NuRD, which interacts and participates with KDM6A to regulate Rac GTPase guanine-nucleotide-exchange-factors GEFs (DOCK5/8) expression and Rac activation in AML cells. DOCK5/8 expression is significantly increased in MBD3loKDM6Ahi patients with a relatively poor survival and pharmacological inhibition of DOCK signaling selectively attenuates AML cell survival. Together our results illustrate a hitherto unidentified epistasis between NuRD and KDM6A towards maintenance of oncogenic gene expression in AML.

Perspectives