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. As the first leading cause of blood cancer death, Acute myeloid leukemias are 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.
► 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. Dr. Puissant’s 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.
► 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. One of the most recent improvement in the area of AML treatment was the use of the FLT3 inhibitor, Midostaurin, in combination with chemotherapy to prolong FLT3-mutated patient’s survival. This suggests that any kind of new therapy, even targeted, that may be found to treat AML patients, will be inevitably used in combination with conventional chemotherapy. By a large scale pooled in vivo shRNA screening, Puissant’s team 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.
► 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. Puissant’s 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.