Molecular Pathology


Hugues DE THÉ
Collège de France courses




Valentina CRIPPA M2 student

Thassadite DIRAMI PhD, IR





Fang QIU Postdoc



Meet the team


Pierre BERCIER PhD Student

Brigitte LAFOND Secretariat



Domitille REROLLE PhD Student


Hsin-Chieh WU Postdoc

Collège de France


Julien ABLAIN PhD Student

Shirine BENHENDA Postdoc

Juliane HALFTERMEYER PhD Student





Muege OGRUNC Postdoc


Kim RICE Postdoc

Umut SAHIN Postdoc


Hao YUAN Postdoc



APL pathogenesis
Acute Promyelocytic Leukaemia, APL, is a simple model of cancer, as it appears to be primarily a monogenic disease. At the biological level, the hallmark t(15,17) translocation leads to fusion between two genes, encoding a PML/RARA fusion protein that initiates APL in mice. Clinical trials have identified two highly efficient drugs, retinoic acid (RA) and arsenic, which we have shown to target PML/RARA and constitute oncogene-targeted therapies (de Thé, 2010). Clinically, RA differentiates APL blasts into granulocytes, a finding that gave rise to the first example of differentiation therapy (de Thé, 2018). The effects of arsenic on APL cells result from a combination of differentiation and apoptosis. PML/RARA is a transcriptional repressor that inhibits myeloid differentiation and enhances the survival and proliferation of early myeloid progenitors. PML/RARA homo-dimerisation through the coiled-coil of PML was proposed to be the primary basis for repression via enhanced binding of co-repressors. Subsequent studies have stressed importance of the following steps for both transcriptional repression and transformation in primary cells:
– sumoylation of the PML moiety of PML/RARA,
– recognition of non-canonical binding sites,
– binding to RXR.
Moreover, as shown below, PML/RARA disrupts PML nuclear bodies, highlighting novel links between nuclear organisation and oncogenesis.

RA-induced reversion of PML/RARA transcriptional repression and gene re-activation were initially thought to be the molecular basis for the therapeutic effect of RA. Yet, this model could not explain the action of arsenic (de Thé and Chen, 2010). In fact, RA both activates transcription and degrades the PML/RARA fusion via the proteasome. Importantly, arsenic also induces proteasome-dependent degradation of both PML and PML/RARA, identifying a major and unexpected similarity between the two agents.
We have demonstrated that while leukemic promyelocytes rapidly differentiate into granulocytes, the leukaemia initiating cells (LIC) only slowly disappear. We have also provided pharmacological and genetic evidence that the fate of these two cell populations can be fully uncoupled (de Thé et al., 2017). While transcriptional activation through PML/RARA clearly accounts for induction of differentiation, PML/RARA degradation by RA and/or arsenic explains LIC clearance and disease eradication. The latter occurs through the reformation of PML Nuclear bodies, the activation of P53 and senescence (Ablain et al., 2014). As we had initially shown in mice (Lallemand-Breitenbach et al., 1999), most APL patients are now cured with the RA/arsenic association, which synergistically degrades PML/RARA and reforms PML NBs (Ablain et al., 2014; Lo-Coco et al., 2013). The key role of PML nuclear bodies in the cure of APL patients was established by the discovery of PML mutations in therapy resistant patients (Lehmann-Che et al., 2014, 2018). Thus, PML is the final effector of targeted cure of APLs.
PML nuclear bodies
PML is the key organiser of PML nuclear bodies (NBs), nuclear matrix-associated small spherical compartments, which recruit a growing number of partner proteins (Lallemand-Breitenbach and de Thé, 2010; Lallemand-Breitenbach and de Thé, 2018). PML and NBs fine-tune a wide variety of processes (senescence, metabolism, self-renewal, apoptosis), most likely through facilitation of partner protein post-translational modifications, resulting in partner sequestration, activation or degradation. PML NBs came to the front stage with our observation that the oncogenic PML/RARA protein disrupts them in a treatment-reversible manner. Our interest was further supported when we found that NBs are indeed required for APL cure by the RA/Arsenic combination (Ablain et al., 2014). PML NBs are regulated by multiple cellular stresses: viral infection, DNA-damage, transformation, oxidative stress. Interestingly, we have identified PML as the first protein degraded by a SUMO-initiated, ubiquitin-mediated proteolysis pathway initiated by direct arsenic binding and disulphide-initiated dimerization (Jeanne et al., 2010; Lallemand-Breitenbach et al., 2008; Lallemand-Breitenbach et al., 2001). These studies highlight the intimate connexions between PML NBs and protein degradation.

From a cell biology perspective, we have dissected the biochemical assembly of PML NBs, we implicated initial PML oxidation, followed by it conjugation by SUMO and partner recruitment through their SIMs (Sahin et al., 2014). In that respect, while Pml-/- mice are devoid of NBs, develop normally and live well, we demonstrated that redox signalling and response to oxidative stress are profoundly altered in Pml-/- mice (Niwa-kawakita et al., 2017).
The current objectives of the group are
i) To clarify the genetic determinants for APL transformation in vivo and therapy response, in particular through the functional analysis of PML knock-in mutants in vivo
ii) To decipher the mechanism of PML-driven senescence in vivo
iii) To explore the implication of PML in interferon response, redox signaling and partner post-translational modifications.
Some key references
► Ablain, J., Rice, K., Soilihi, H., de Reynies, A., Minucci, S., and de Thé, H. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat. Med., 2014. 20, 167-174.
► De Thé, H. Differentiation therapy revisited. Nat. Rev. Cancer, 2018.  18, 117-127.
► De Thé, H., and Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat. Rev. Cancer, 2010. 10, 775-783.
► De Thé, H., Pandolfi, P.P., and Chen, Z. Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. Cancer Cell, 2017.  32, 552-560.
► Jeanne, M., Lallemand-Breitenbach, V., Ferhi, O., Koken, M., Le Bras, M., Duffort, S., Peres, L., Berthier, C., Soilihi, H., Raught, B., et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell, 2010. 18, 88-98.
► Lallemand-Breitenbach, V., and de Thé, H. PML nuclear bodies: from architecture to function. Curr. Opin. Cell Biol. 2018.  52, 154-161.
► Lallemand-Breitenbach, V., and de Thé, H. PML nuclear bodies. Cold Spring Harb Perspect Biol 2, 2010. 2(5): a000661.
► Lallemand-Breitenbach, V., Jeanne, M., Benhenda, S., Nasr, R., Lei, M., Peres, L., Zhou, J., Zhu, J., Raught, B., and de Thé, H. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat. Cell Biol. 2008. 10, 547-555.
► Lallemand-Breitenbach, V., Zhu, J., Puvion, F., Koken, M., Honore, N., Doubeikovsky, A., Duprez, E., Pandolfi, P.P., Puvion, E., Freemont, P., et al. Role of Promyelocytic Leukemia (PML) Sumolation in Nuclear Body Formation, 11S Proteasome Recruitment, and As(2)O(3)-induced PML or PML/Retinoic Acid Receptor alpha Degradation. J. Exp. Med. 2001. 193, 1361-1372.
► Lallemand-Breitenbach, V., Guillemin, M.-C., Janin, A., Daniel, M.-T., Degos, L., Kogan, S.C., Bishop, J.M., and de Thé, H. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J. Exp. Med. 1999.  189, 1043-1052.
► Lehmann-Che, J., Bally, C., and de Thé, H. Therapy resistance in APL. New Engl. J. Med.,  2014. 371, 1171-1172.
► Lo-Coco, F., Avvisati, G., Vignetti, M., Thiede, C., Orlando, S.M., Iacobelli, S., Ferrara, F., Fazi, P., Cicconi, L., Di Bona, E., et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New Engl. J. Med., 2013.  369, 111-121.
► Niwa-Kawakita, M., O. Ferhi, H. Soilihi, M. Le Bras, V. Lallemand-Breitenbach, and H. de Thé. PML is a ROS sensor activating p53 upon oxidative stress. J. Exp. Med., 2017. 214(11): p. 3197-3206.
► Sahin, U., de Thé, H., and Lallemand-Breitenbach, V. PML nuclear bodies: assembly and oxidative stress-sensitive sumoylation. Nucleus, 2014.  5, 499-507.
The group’s primary interest is to explore the connections between genetic events driving cancer development and response to therapy. In acute promyelocytic leukemia (APL), we have made key contributions to the understanding of the basis for leukemic transformation by the PML/RARA fusion protein and arsenic or retinoic acid therapy. Our studies have revealed that both agents bind PML/RARA and thus constitute targeted therapies that both initiate PML/RARA degradation by the proteasome. We then demonstrated the key role of PML/RARA degradation by retinoic acid and arsenic in APL responses. Recently, in work supported by the ERC, we have provided conclusive evidence in mouse models and in patients that, downstream of PML/RARA degradation, re-organization of PML nuclear bodies (NBs) and the subsequent activation of P53 are the key contributors to therapy response by a mechanism with many features of senescence.

The group has thus invested significant efforts to decipher the normal function of PML NBs, as well as the assembly of these membrane-less subnuclear domains. We have demonstrated that PML NBs are directly implicated in response to oxidative stress. This likely reflects the fact that PML is a redox-sensitive protein whose polymerization yields the external scaffolding shell of NBs. The latter drives recruitment of partner proteins by sumoylated PML. The transient sequestration of partners, as well as the UBC9 sumoylation enzyme was then proposed to allow their conjugation by SUMO. These proteins may subsequently be degraded by the SUMO-initiated, ubiquitin activated proteolysis pathway that we discovered when analysis PML degradation by arsenic.

Our current work, supported by ERC (2019-2024), aims at harnessing PML nuclear bodies to activate a PML/P53 senescence axis, notably in diseases previously shown to be responsive to interferons, a cytokine that massively induces PML expression. This involves a throughout exploration of PML biology, modeling its polymerization into membrane-less droplets and analysis of partner’s fate. We are also investigating the biological basis of therapy response in other leukemia/treatment pairs, notably focusing on RARA and NPM1c.
Collectively, our work is at the rich interface between very basic issues of regulation of gene expression, post-translational modifications, cell biology, in the context of human cancer biology and therapy. The strategies that derive from the models generated in the lab have been successfully implemented in APL patients and we now aim at new breakthroughs in other conditions.
Main publications – 2014-2020
► Geoffroy MC, de Thé H. Classic and Variants APLs, as Viewed from a Therapy Response. Cancers (Basel). 2020 Apr 14;12(4).
► Marçais A, Cook L, Witkover A, Asnafi V, Avettand-Fenoel V, Delarue R, Cheminant M, Sibon D, Frenzel L, de Thé H, Bangham CRM, Bazarbachi A, Hermine O, Suarez F. Arsenic trioxide (As2O3) as a maintenance therapy for adult T cell leukemia/lymphoma. Retrovirology. 2020 Mar 21;17(1):5.
► Paubelle E, Zylbersztejn F, Maciel TT, Carvalho C, Mupo A, Cheok M, Lieben L, Sujobert P, Decroocq J, Yokoyama A, Asnafi V, Macintyre E, Tamburini J, Bardet V, Castaigne S, Preudhomme C, Dombret H, Carmeliet G, Bouscary D, Ginzburg YZ, de Thé H, Benhamou M, Monteiro RC, Vassiliou GS, Hermine O, Moura IC. Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow. Cell Rep. 2020 Jan 21;30(3):739-754.e4.
► Auvin S, Öztürk H, Abaci YT, Mautino G, Meyer-Losic F, Jollivet F, Bashir T, de Thé H, Sahin U. A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells. Life Sci Alliance. 2019 Aug 20;2(4). pii: e201800213.
► McKenzie MD, Ghisi M, Oxley EP, Ngo S, Cimmino L, Esnault C, Liu R, Salmon JM, Bell CC, Ahmed N, Erlichster M, Witkowski MT, Liu GJ, Chopin M, Dakic A, Simankowicz E, Pomilio G, Vu T, Krsmanovic P, Su S, Tian L, Baldwin TM, Zalcenstein DA, DiRago L, Wang S, Metcalf D, Johnstone RW, Croker BA, Lancaster GI, Murphy AJ, Naik SH, Nutt SL, Pospisil V, Schroeder T, Wall M, Dawson MA, Wei AH, de Thé H, Ritchie ME, Zuber J, Dickins RA. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia. Cell Stem Cell. 2019 Aug 1;25(2):258-272.e9.
Primitive macrophages are dispensable for HSPC mobilization and definitive hematopoiesis. Yuan H, Gao S, Chen H, Liu X, Zhou J, de Thé H, Zhu J. Blood. 2019 Aug 29;134(9):782-784.
► Wang L, Gao S, Wang H, Xue C, Liu X, Yuan H, Wang Z, Chen S, Chen Z, de Thé H, Zhang Y, Zhang W, Zhu J, Zhou J. Interferon regulatory factor 2 binding protein 2b regulates neutrophil versus macrophage fate during zebrafish definitive myelopoiesis. Haematologica. 2020 Jan 31;105(2):325-337.
► Yang, R.M., Tao, J., Zhan, M., Yuan H., Wang HH, Chen SJ, Chen Z, de Thé H, Zhou J, Guo Y, Zhu J. TAMM41 is required for heart valve differentiation via regulation of PINK-PARK2 dependent mitophagy . Cell Death Differ. 2019 Nov;26(11):2430-2446.
► Gentric G., Kieffer Y., Mieulet V., Goundiam O., Bonneau C., Nemati F., Hurbain I., Raposo G., Popova T.,  Stern M.H., Lallemand-Breitenbach V., Muller S., Caneque T., Rodriguez R., Vincent-Salomon A., de Thé H., Rossignol R. and Mechta-Grigoriou F. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metab. 2019 29(1): 156-173 e110.
► Esnault, C., R. Rahme, K. L. Rice, C. Berthier, C. Gaillard, S. Quentin, A. L. Maubert, S. Kogan and H. de Thé. FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias. Blood. 2019 133(13): p. 1495-1506.
► McKenzie MD, Ghisi M, Oxley EP, Ngo S, Cimmino L, Esnault C, Liu R, Salmon JM, Bell CC, Ahmed N, Erlichster M, Witkowski MT, Liu GJ, Chopin M, Dakic A, Simankowicz E, Pomilio G, Vu T, Krsmanovic P, Su S, Tian L, Baldwin TM, Zalcenstein DA, DiRago L, Wang S, Metcalf D, Johnstone RW, Croker BA, Lancaster GI, Murphy AJ, Naik SH, Nutt SL, Pospisil V, Schroeder T, Wall M, Dawson MA, Wei AH, de Thé H, Ritchie ME, Zuber J, Dickins RA. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia. Cell Stem Cell. 2019  201925(2):258-272.
► Wang, P., S. Benhenda, H. Wu, V. Lallemand-Breitenbach, T. Zhen, F. Jollivet, L. Peres, Y. Li, S. J. Chen, Z. Chen, H. de Thé and G. Meng. RING tetramerization is required for nuclear body biogenesis and PML sumoylation. Nat Commun 2018  9 (1): 1277.
► Wang, L., X. Liu, H. Wang, H. Yuan, S. Chen, Z. Chen, H. de Thé, J. Zhou and J. Zhu RNF4 regulates zebrafish granulopoiesis through the DNMT1-C/EBPalpha axis. FASEB J. 2018 32(9): 4930-4940.
► Lehmann-Che, J., C. Bally, E. Letouze, C. Berthier, H. Yuan, F. Jollivet, L. Ades, B. Cassinat, P. Hirsch, A. Pigneux, M. J. Mozziconacci, S. Kogan, P. Fenaux and H. de Thé Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia. Nat Commun 2018 9(1): 2047.
► Lallemand-Breitenbach, V. and H. de Thé “PML nuclear bodies: from architecture to function.” Curr Opin Cell Biol 2018 52: 154-161.
► Gaillard, C., S. Surianarayanan, T. Bentley, M. R. Warr, B. Fitch, H. Geng, E. Passegue, H. de Thé and S. C. Kogan Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia. Blood Adv. 2018 2 (19): 2462-2466.
► Gachet, S., T. El-Chaar, D. Avran, E. Genesca, F. Catez, S. Quentin, M. Delord, G. Therizols, D. Briot, G. Meunier, L. Hernandez, M. Pla, W. K. Smits, J. G. Buijs-Gladdines, W. Van Loocke, G. Menschaert, I. Andre-Schmutz, T. Taghon, P. Van Vlierberghe, J. P. Meijerink, A. Baruchel, H. Dombret, E. Clappier, J. J. Diaz, C. Gazin, H. de Thé, F. Sigaux and J. Soulier. Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation. Cancer Discov. 2018 8(12): 1614-1631.
► De Thé, H. Differentiation therapy revisited. Nat Rev Cancer 2018 18(2): 117-127.
► Ribet, D., V. Lallemand-Breitenbach, O. Ferhi, M. A. Nahori, H. Varet, H. de Thé and P. Cossart. Promyelocytic Leukemia Protein (PML) Controls Listeria monocytogenes Infection. MBio 2017  8(1).
► Tessier, S., N. Martin-Martin, H. de Thé, A. Carracedo and V. Lallemand-Breitenbach Promyelocytic Leukemia Protein, a Protein at the Crossroad of Oxidative Stress and Metabolism. Antioxid Redox Signal 2017 26(9): 432-444.
► Niwa-Kawakita, M., O. Ferhi, H. Soilihi, M. Le Bras, V. Lallemand-Breitenbach and H. de Thé PML is a ROS sensor activating p53 upon oxidative stress. J Exp Med. 2017 214(11): 3197-3206.
► De Thé, H., P. P. Pandolfi and Z. Chen. Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. Cancer Cell 2017 32(5): 552-560.
► Ferhi, O., L. Peres, S. Tessier, H. de Thé and V. Lallemand-Breitenbach Comment on SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML. Sci Signal 2016 9(440): tc1.
► Dvorkina, M., V. Nieddu, S. Chakelam, A. Pezzolo, S. Cantilena, A. P. Leite, O. Chayka, T. Regad, A. Pistorio, A. R. Sementa, A. Virasami, J. Barton, X. Montano, T. Lechertier, N. Brindle, D. Morgenstern, M. Lebras, A. J. Burns, N. J. Saunders, K. Hodivala-Dilke, L. Bagella, H. de Thé, J. Anderson, N. Sebire, V. Pistoia, A. Sala and P. Salomoni. A Promyelocytic Leukemia Protein-Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma. Clin Cancer Res 2016 22(13): 3398-3409.
► Ablain, J., B. Poirot, C. Esnault, J. Lehmann-Che and H. de Thé. p53 as an Effector or Inhibitor of Therapy Response. Cold Spring Harb Perspect Med  2016  6(1): a026260.
► Yuan, H., T. Zhang, X. Liu, M. Deng, W. Zhang, Z. Wen, S. Chen, Z. Chen, H. de Thé, J. Zhou and J. Zhu. Sumoylation of CCAAT/enhancer-binding protein alpha is implicated in hematopoietic stem/progenitor cell development through regulating runx1 in zebrafish. Sci Rep. 2015 5: 9011.
► Ivanschitz, L., Y. Takahashi, F. Jollivet, O. Ayrault, M. Le Bras and H. de Thé PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence. Proc Natl Acad Sci U S A 2015. 112(46): 14278-14283.
► El Hajj, H., Z. Dassouki, C. Berthier, E. Raffoux, L. Ades, O. Legrand, R. Hleihel, U. Sahin, N. Tawil, A. Salameh, K. Zibara, N. Darwiche, M. Mohty, H. Dombret, P. Fenaux, H. de Thé and A. Bazarbachi (2015). Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood 125(22): 3447-3454.
► De Thé, H. Lessons taught by APL cure. Lancet 2015 18;386(9990):247-8
► Dassouki, Z., U. Sahin, H. El Hajj, F. Jollivet, Y. Kfoury, V. Lallemand-Breitenbach, O. Hermine, H. de Thé and A. Bazarbachi. ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation. Blood 2015 125(3): 474-482.
► Bally, C., A. Renneville, C. Preudhomme, M. Legrand, L. Ades, H. de Thé, P. Fenaux and J. Lehmann-Che.  Comparison of TP53 mutations screening by functional assay of separated allele in yeast and next-generation sequencing in myelodysplastic syndromes. Leuk Res. 2015 pii: S0145-2126(15)30344-1.
► Vitaliano-Prunier, A., J. Halftermeyer, J. Ablain, A. de Reynies, L. Peres, M. Le Bras, D. Metzger and H. de Thé. Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation. Blood 2014 124(25): 3772-3780.
► Sahin, U., V. Lallemand-Breitenbach and H. de Thé. PML nuclear bodies: regulation, function and therapeutic perspectives. J Pathol 2014 234(3): 289-291.
► Sahin, U., O. Ferhi, M. Jeanne, S. Benhenda, C. Berthier, F. Jollivet, M. Niwa-Kawakita, O. Faklaris, N. Setterblad, H. de Thé and V. Lallemand-Breitenbach. Oxidative stress-induced assembly of PML nuclear bodies controls sumoylation of partner proteins. J Cell Biol 2014 204(6): 931-945.
► Sahin, U., O. Ferhi, X. Carnec, A. Zamborlini, L. Peres, F. Jollivet, A. Vitaliano-Prunier, H. de Thé and V. Lallemand-Breitenbach. Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication. Nature communications 2014 19: 4187.
► Lehmann-Che, J., C. Bally and H. de Thé. Therapy resistance in APL. New Engl. J. Med. 2014 371: 1171-1172.
► Bally, C., L. Ades, A. Renneville, M. Sebert, V. Eclache, C. Preudhomme, M. J. Mozziconacci, H. de Thé, J. Lehmann-Che and P. Fenaux. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk Res 2014 38(7): 751-755.
► Ablain, J., K. Rice, H. Soilihi, A. de Reynies, S. Minucci and H. de Thé Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med 2014 20(2): 167-174.
► Ablain, J. and H. de Thé. Retinoic acid signaling in cancer: The parable of acute promyelocytic leukemia. Int J Cancer 2014 135(10): 2262-2272.