Page 268 - Haematologica March 2020

F. Chatonnet et al.
cer and favor tumorigenesis induced by the Epstein-Barr virus-derived latent membrane protein 1.48,49 FAM72 genes are highly expressed in TP53 mutated cancer cells, whose growth has been shown to be dependent on FAM72D.50,51 Interestingly, cancer cell growth dependency on FAM72D has also been demonstrated for cells with mutated or copy number variants of p300, p19Arf and CDKI2A,51 suggest- ing that FAM72D is required for the growth of different cancer types. Corroborating the tumorigenic potential of FAM72 proteins, two insertional mutagenesis screens in mouse identified the mouse SRGAP2/FAM72A locus as a driver of chronic myeloid leukemia progression and growth factor-independent leukemogenesis.52,53 Hence, TET-mediated demethylation of the FAM72D upstream region is likely coupled to the proliferation potential of MM cells.
We have defined here a MM-specific hydroxymethy- lome that favors a survival/proliferation program relying, at least in part, on the cooperative actions of enhancers and super-enhancers controlling FAM72D, GAS2, DEP-
TOR and MYC expression (Figure 6). In accordance with the observation that FAM72 expression is predictive to the sensitivity of MM cells to different treatments, its evalua- tion in patients could help to tailor therapy.
Funding
GS was supported by a grant from La Ligue Contre le Cancer (Grand Ouest committee). The work was partially funded by the hematology laboratory of Rennes University Hospital. AP was supported by PhD training grants from Région Bretagne and Ligue Nationale Contre le Cancer. JM was supported by grants from French INCA (Institut National du Cancer) Institute (PLBIO15-256), PLBIO2018-PIT-MM, LR-FEDER Hemodiag, Fondation de France (201400047510), ITMO Cancer (MM&TT), SIRIC Montpellier (INCa-DGOS-Inserm 6045) and Labex EpiGenMed.
Acknowledgments
The authors thank the BioGenouest GEH sequencing plate- form (https://geh.univ-rennes1.fr/) from the UMS Biosit.
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