ORCID Profile
0000-0003-0583-9879
Current Organisation
Cancer Research Center of Toulouse (CRCT) (INSERM U1037- CNRS UMR5071)
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Publisher: American Society of Hematology
Date: 30-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 10-2020
DOI: 10.1158/2159-8290.CD-19-1008
Abstract: Extracellular ATP and CD39–P2RY13–cAMP–OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML. This article is highlighted in the In This Issue feature, p. 1426
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.STEM.2019.07.001
Abstract: Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.CCELL.2016.05.019
Abstract: E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8 ) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8 ) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-05-2016
DOI: 10.1126/SCITRANSLMED.AAD3099
Abstract: The combination of a SMAC mimetic and a caspase inhibitor kills AML cells by inducing necroptosis.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1038/S41467-021-26849-W
Abstract: Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.CCELL.2016.01.006
Abstract: Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
Publisher: American Society of Hematology
Date: 29-05-2014
DOI: 10.1182/BLOOD-2014-03-561456
Abstract: Loss of Id2 in T cells results in overexpression of IL-10 during influenza infection and GVHD and protects against GVHD immunopathology. Id2 represses the direct E2A-mediated activation of the Il10 locus in effector T cells.
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Society of Hematology
Date: 27-02-2014
DOI: 10.1182/BLOOD-2013-03-488114
Abstract: HDACi-mediated differentiation therapy is a potent and molecularly rational treatment strategy in t(8 ) AML.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2014
DOI: 10.1038/LEU.2014.134
Publisher: Springer Science and Business Media LLC
Date: 12-04-2018
Location: France
Location: Australia
No related grants have been discovered for Margherita Ghisi.