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Nat Commun. 2019 Aug 22;10(1):3789. doi: 10.1038/s41467-019-11746-0.

B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis.

Author information

1
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
2
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China. guoyumeng@shsmu.edu.cn.

Abstract

ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 μm in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 Å) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RARα (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RARα-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.

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