The Puissant Lab located at the Institute of Hematology at Saint-Louis Medical Center in Paris, is focused on the study of Acute Myeloid Leukemias (AML). As the first leading cause of blood cancer death, AML is highly refractory to all forms of treatment and novel approaches are urgently needed. Our lab is focused on understanding the complex biology of this deadly blood cancer to develop novel therapeutic approaches as well as to promote response to existing chemotherapy. Specifically, we have taken a comprehensive approach to decipher altered cellular responses of leukemic cells using large-scale screening strategies in pre-clinical models.
Using In Vivo Screening Technology to Decipher New Oncogenic Pathways in AML
► AML development does not only depend on accumulation of genetic alterations; it also relies on adaptive mechanisms initiated in the leukemic progenitor cells to overgrow within their microenvironment. Investigating this disease as closely as possible to human pathology, then, requires use of preclinical AML mouse models in which leukemic cells are transplanted into their bone marrow microenvironment to be studied. Our group develops transplantable mouse models of AML, which they screen using shRNA libraries in order to identify candidate genes involved in leukemia cell proliferation in bone marrow. Using large scale genomic experiments such as Chip- and RNA-sequencing, they define molecular mechanisms by which candidate target genes impact cell proliferation and survival, and they are therefore able to delineate efficient therapeutic strategies to target pathways of interest in AML.
Extending the Use of Screening Technology to Decipher Mechanisms of Chemoresistance in AML
► Although global sequencing efforts pinpointed several mutations in AML that could be druggable by specific inhibitors, the therapeutic options currently available to treat patients with AML are still restricted to the use of conventional chemotherapy based on the combination of anthracyclines with cytarabine. This therapeutic regimen can achieve sustained remission and can even cure some patients; however, many patients relapse with a progressively more chemoresistant disease. By implementing large-scale pooled in vivo screening approaches, we seek to identify new therapeutic targets that would improve the action of standard chemotherapy while reducing its global toxicity. Identification of such new targets will diminish the risk of the minimal residual disease that occurs in more than half of patients with AML.
Establishing Mechanisms of Leukemic Stem Cell Maintenance in AML
► Malignant stem cells have recently been described as the source of several types of human cancer. These unique cell types are typically rare and possess properties that are distinct from most other tumor cells. The properties of leukemic stem cells (LSCs) make them intrinsically more resistant to chemotherapy drugs and therefore, LSCs represent a reservoir able to fuel relapse AML disease. One important driver of this stemness state is the oncogene c-myc which controls a vast network of genes which all participate in stemness maintenance. Our laboratory uses a niche-like culture method which allows the maintenance of LSCs in order to identify genes from the c-myc network that are bona fide regulators of LSCs’ function. Subsequent functional analyses of these candidate genes in AML should bring the light on new therapeutic strategies intended to eradicate this particular hard-to-treat subpopulation of LSCs, and then prevent disease relapse.
Toward Improvement of AML Patient Clinical Outcome
In order to translate our research effort into major clinical improvement of AML patient outcome, we develop tools to foster precision medicine. Currently, prognostic evaluation and therapeutic decisions mostly rely on genetic features of the leukemia determined on bulk sequencing of a bone marrow sample. We study the influence of intra-tumor genetic heterogeneity on resistance to chemotherapy. We also develop flow cytometry based assays such as high-throughput high-content ex vivo drug screening of primary leukemic specimens to prioritize anti-leukemic drugs or combinations for each patient.
► Roux B, Vaganay C, Vargas JD, Alexe G, Benaksas C, Pardieu B, Fenouille N, Ellegast JM, Malolepsza E, Ling F, Sodaro G, Ross L, Pikman Y, Conway AS, Tang Y, Wu T, Anderson DJ, Le Moigne R, Zhou HJ, Luciano F, Hartigan CR, Galinsky I, DeAngelo DJ, Stone RM, Auberger P, Schenone M, Carr SA, Guirouilh-Barbat J, Lopez B, Khaled M, Lage K, Hermine O, Hemann MT, Puissant A*, Stegmaier K*, Benajiba L*. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor. *Co-last authors. Science Translational Medicine. 2021 Mar.
► Pikman Y, Tasian SK, Sulis ML, Stevenson K, Blonquist TM, Apsel Winger B, Cooper TM, Pauly M, Maloney KW, Burke MJ, Brown PA, Gossai N, McNeer JL, Shukla NN, Cole PD, Kahn JM, Chen J, Barth MJ, Magee JA, Gennarini L, Adhav AA, Clinton CM, Ocasio-Martinez N, Gotti G, Li Y, Lin S, Imamovic A, Tognon CE, Patel T, Faust HL, Contreras CF, Cremer A, Cortopassi WA, Garrido Ruiz D, Jacobson MP, Dharia NV, Su A, Robichaud AL, Saur Conway A, Tarlock K, Stieglitz E, Place AE, Puissant A, Hunger SP, Kim AS, Lindeman NI, Gore L, Janeway KA, Silverman LB, Tyner JW, Harris MH, Loh ML, Stegmaier
► K. Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory or High-risk Leukemias: A Report from the LEAP Consortium. Cancer Discovery. 2021 Feb.
► Su A, Ling F, Vaganay C, Sodaro G, Benaksas C, Dal Bello R, Forget A, Pardieu B, Lin KH, Rutter JC, Bassil CF, Fortin G, Pasanisi J, Antony-Debré I, Alexe G, Benoist JF, Pruvost A, Pikman Y, Qi J, Schlageter MH, Micol JB, Roti G, Cluzeau T, Dombret H, Preudhomme C, Fenouille N, Benajiba L, Golan HM, Stegmaier K, Lobry C, Wood KC, Itzykson R, Puissant A. The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies. Cancer Discovery. 2020 Dec.
► Schmoellerl J, Barbosa IAM, Eder T, Brandstoetter T, Schmidt L, Maurer B, Troester S, Pham HTT, Sagarajit M, Ebner J, Manhart G, Aslan E, Terlecki-Zaniewicz S, Van der Veen C, Hoermann G, Duployez N, Petit A, Lapillonne H, Puissant A, Itzykson R, Moriggl R, Heuser M, Meisel R, Valent P, Sexl V, Zuber J, Grebien F. CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia. Blood. 2020 Jul.
► Lin KH, Rutter JC, Xie A, Winn A, Pardieu B, Dal Bello R, Forget A, Itzykson R, Yeong-Ran A, Ziwei D, Sobhan RT, Anderson GR, Singleton KR, Decker AE, Winter PS, Locasale J, Crawford L, Puissant A*, Wood KC*. Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap. Nature Genetics. In press. *Co-last authors.
► Itzykson R, Duployez N, Fasan A, Decool G, Marceau-Renaut A, Meggendorfer M, Jourdan E, Petit A, Lapillonne H, Micol JB, Cornillet-Lefebvre P, Ifrah N, Leverger G, Dombret H, Boissel N, Haferlach T, Preudhomme C. Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia. Blood. 2018 Jul 12;132(2):187-196.
► Fenouille N, Bassil CF, Ben-Sahra I, Alexe G, Benajiba L, Ramos A, Pikman Y, Burgess MR, Qing L, Luciano F, Auberger P, Galinsky I, DeAngelo DJ, Stone RM, Zhang Y, Perkins AS, Shannon K, Hemann MT, Stegmaier K*, Puissant A*. Targeting creatine kinase pathway in EVI1-positive Leukemia. Nature Medicine. 2017 Mar;23(3):301-313. *Co-last authors.
► Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, Du J, Kazi JU, Luciano F, Rönnstrand L, Kung AL, Aster JC, Galinsky I, Stone RM, DeAngelo DJ, Hemann MT, Stegmaier K. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014 Feb 10;25(2):226-42.
► Puissant A*, Frumm SM*, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, Stegmaier K. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23. *Co-first authors.
► Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, Berthon C, Adès L, Fenaux P, Beyne-Rauzy O, Vey N, Braun T, Haferlach T, Dreyfus F, Cross NC, Preudhomme C, Bernard OA, Fontenay M, Vainchenker W, Schnittger S, Birnbaum D, Droin N, Solary E. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013 Jul 1;31(19):2428-36.
► Miller PG, Al-Shahrour F, Hartwell KA, Chu LP, Järås M, Puram RV, Puissant A, Callahan KP, Ashton J, McConkey ME, Poveromo LP, Cowley GS, Kharas MG, Labelle M, Shterental S, Fujisaki J, Silberstein L, Alexe G, Al-Hajj MA, Shelton CA, Armstrong SA, Root DE, Scadden DT, Hynes RO, Mukherjee S, Stegmaier K, Jordan CT, Ebert BL. In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell. 2013 Jul 8;24(1):45-58.
PhD, Postdoc fellow