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Transcriptional control and signal transduction, cell cycle

PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias

Leukemia volume 31, pages 1975–1986 (2017)Cite this article

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Abstract

It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5–10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single ‘mutated’ gene network.

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Gene Expression Omnibus

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Acknowledgements

We are grateful to: AJ Capobianco for providing reagents and suggestions for the screen; F Bianchi and PP Di Fiore for discussion and suggestions; B Amati and G Nucifora for providing plasmids for cooperation studies; P Dalton for editing the manuscript. This study was supported by AIRC (Associazione Italiana Ricerca sul Cancro; IG10253 (PGP); IG2014 and AIRC 5 × 1000 (AB)) and the Italian Ministry of Health (PGP).

Author contributions

CR designed and performed all experiments, unless specified and wrote the manuscript. AB, LR, LL and GEMM performed bioinformatics analyses. AMG participated in experiments of cooperation. ES performed histopathological and immunohistochemical analyses. GD, MM, VB and DDB performed Netview analysis. SL, FL-C, VR, AB, OS and AR supplied clinical samples. PGP conceived and supervised the project and co-wrote the manuscript.

Author information

Author notes

  1. A Brozzi

    Present address: 13Current Address: GSK Vaccines, Siena, Italy.,

  2. G Dharmalingam

    Present address: 14Current Address: Imperial College London, Hammersmith Hospital Campus, London, UK.,

Authors and Affiliations

  1. Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy

    C Ronchini, L Riva & G E M Melloni

  2. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    A Brozzi, L Luzi, A M Gruszka & P G Pelicci

  3. Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy

    E Scanziani

  4. Dipartimento di Scienze Veterinarie e Sanità Pubblica, Università degli Studi di Milano, Milan, Italy

    E Scanziani

  5. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy

    G Dharmalingam, M Mutarelli & D di Bernardo

  6. Department of Electrical Engineering and Information Technology, University of Naples ‘Federico II’, Naples, Italy

    V Belcastro

  7. Department of Biomedicine and Prevention, University of ‘Rome Tor Vergata’, Rome, Italy

    S Lavorgna & F Lo-Coco

  8. Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, Rome, Italy

    S Lavorgna & F Lo-Coco

  9. Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy

    V Rossi

  10. Hematology and Bone Marrow Transplant Unit of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

    O Spinelli & A Rambaldi

  11. Clinica Pediatrica, Università di Milano Bicocca,

    A Biondi

  12. Ospedale San Gerardo, Monza, Italy

    A Biondi

  13. Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy

    P G Pelicci

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  1. C Ronchini
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Correspondence to C Ronchini or P G Pelicci.

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Ronchini, C., Brozzi, A., Riva, L. et al. PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias. Leukemia 31, 1975–1986 (2017). https://doi.org/10.1038/leu.2016.386

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