Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation.

Bappaditya Chandra,Chunxu Qu,Khaled Khairy,Priyanka Dogra,Charles G Mullighan,Qingsong Gao,Sherif Abdelhamed,David W Baggett,Jeffery M Klco,Swati Kinger,Anna Medyukhina,Richard W Kriwacki,Stanley Pounds,Brittany J Pioso,Jingjing Chen,Mylene C Ferrolino,Cristina Mecucci,Swarnendu Tripathi,Ilaria Iacobucci,Huiyun Wu,Nicole L Michmerhuizen,Simranjot Bawa,Danika Di Giacomo,Carolyn Maslanka,Scott D Gorman,Diana M Mitrea,Hazheen K Shirnekhi,Cheon‐Gil Park ,Michael R H White

doi:10.1158/2159-8290.cd-21-0674

Abstract

We show that homotypic and heterotypic mechanisms of LLPS control NUP98-HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. This article is highlighted in the In This Issue feature, p. 873.

Highlights

Chromosomal translocations involving the Nucleoporin 98 (NUP98) gene are observed in various hematologic malignancies and are a hallmark of high-risk childhood leukemias
We propose that G-NHA9 puncta form through liquid-liquid phase separation (LLPS) driven by interactions mediated by the multivalent FG motifs and interactions of the HOXA9 homeodomain with DNA (Fig. 1A)
These results demonstrate that the NUP98-KDM5A fusion oncoproteins (FOs) forms nuclear puncta in human, patient-derived acute myeloid leukemia (AML) cells similar to those observed after viral transduction of mouse lin

Summary

Introduction

Chromosomal translocations involving the Nucleoporin 98 (NUP98) gene are observed in various hematologic malignancies and are a hallmark of high-risk childhood leukemias. NUP98 fusion oncoproteins (FOs) occur in approximately ~5% of all pediatric acute myeloid leukemia (AML) patients [1,2,3,4,5]. NUP98 rearrangement shows increased prevalence within specific AML subtypes, including those with monocytic, megakaryoblastic, and erythroid differentiation 50% of children with chemotherapy-resistant AML bear NUP98 FOs [10], and there are currently no effective targeted therapeutic strategies for these patients. Understanding the molecular mechanism by which NUP98 FOs drive cancer is needed to offer pediatric AML patients opportunities for improved clinical outcomes in the future. The N-terminal portion of the NUP98 protein is an intrinsically disordered region (IDR) enriched in phenylalanine-glycine (FG) motifs [16]

Methods

Results

Conclusion