Françoise PORTEU / Eric SOLARY
From haematopoietic stem cell to myelomonocytic differentiation
From haematopoietic stem cell to myelomonocytic differentiation
KEYWORDS: Hematopoietic stem cells, myeloid cells, bone marrow
Mouse; human
Signaling; DNA repair; differentiation; self-renewal; aging; inflammation; leukemia
Mouse; human
Signaling; DNA repair; differentiation; self-renewal; aging; inflammation; leukemia
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INSERM U1170
Cancer Campus Gustave Roussy, PR1 114 rue Édouard-Vaillant 94805 Villejuif Cedex Email F.Porteu Email E.Soalry Webpage |
.Homeostasis of the hematopoietic compartment is tightly controlled by quiescence, self-renewal and differentiation phases of hematopoietic stem cells (HSCs). Control of DNA damages is a crucial process for HSC functionality as in the long run, it is associated with non-reversible loss of HSC reserve or self-renewal, leading to bone marrow failure or cancer. By inducing the proliferation of HSCs, chronic infection may also enhance the risk to accumulate genomic alterations. Progressive increase in the proinflammatory status occurs with age which may contribute to the loss of HSC function, myeloid differentiation skewing and accumulation of DNA damage that characterize aging. HSCs are regulated through interaction with the niche environment and growth factors controlling the balance between quiescence/proliferation and differentiation. Our team explores how these factors contribute to the HSC responses and the molecular mechanisms that drive myelo-monocytic expansion in response to acute or chronic stresses, either inflammatory or genotoxic. We also explore the mechanisms controlling HSC genomic stability and myeloid differentiation in the context of clonal myelo-monocytic leukemia, a pathology of the elderly characterized by the accumulation of classical monocytes and dysplastic granulocytes in the peripheral blood as a consequence of genetic and epigenetic alterations that affect the HSC.
Our recent results showed that Thrombopoietin (TPO), a niche cytokine that plays a critical role in HSC self-renewal, induces DNA damage repair by directly improving non-homologous end joining DNA repair. Our current work explores how TPO interplays with endogenous and exogenous stress stimuli to maintain HSC self-renewal and their myeloid/lymphoid differentiation balance, in aged mice or in model of premature aging induced by total body irradiation exposure or chronic inflammation, with a particular focus on signaling pathways and epigenetic controls involved in these processes.
We have shown that the ERK signaling pathway controls the expression of the myeloid lineage cytokine macrophage colony-stimulating factor receptor (M-CSFR). We are analyzing the possibility that this pathway might govern myeloid differentiation choice at the level of the HSC and the production of the various mature myeloid effector cell subsets in homeostasis and during chronic inflammation and that it may affect the myelo-monocytic differentiation bias observed in CMML patients. We also study the mechanisms involved in HSC homing and niche retention, with a particular focus on the CXCR4/SDF-1 axis. We have identified a characteristic molecular fingerprint that associates mutations in TET2, ASXL1, SRSF2 and genes involved in the Ras signaling pathway, deciphered the clonal architecture of the CMML, demonstrated the immunosuppressive functions of dysplastic granulocytes, and identified epigenetically deregulated genes that contribute to the disease pathogenesis. Ongoing projects explore functional genetics, the link between genetic and epigenetic abnormalities, alteration of the DNA repair pathways, disease-associated immune alterations, and the role of the microenvironment in disease development and evolution.
Recent publications:
Our recent results showed that Thrombopoietin (TPO), a niche cytokine that plays a critical role in HSC self-renewal, induces DNA damage repair by directly improving non-homologous end joining DNA repair. Our current work explores how TPO interplays with endogenous and exogenous stress stimuli to maintain HSC self-renewal and their myeloid/lymphoid differentiation balance, in aged mice or in model of premature aging induced by total body irradiation exposure or chronic inflammation, with a particular focus on signaling pathways and epigenetic controls involved in these processes.
We have shown that the ERK signaling pathway controls the expression of the myeloid lineage cytokine macrophage colony-stimulating factor receptor (M-CSFR). We are analyzing the possibility that this pathway might govern myeloid differentiation choice at the level of the HSC and the production of the various mature myeloid effector cell subsets in homeostasis and during chronic inflammation and that it may affect the myelo-monocytic differentiation bias observed in CMML patients. We also study the mechanisms involved in HSC homing and niche retention, with a particular focus on the CXCR4/SDF-1 axis. We have identified a characteristic molecular fingerprint that associates mutations in TET2, ASXL1, SRSF2 and genes involved in the Ras signaling pathway, deciphered the clonal architecture of the CMML, demonstrated the immunosuppressive functions of dysplastic granulocytes, and identified epigenetically deregulated genes that contribute to the disease pathogenesis. Ongoing projects explore functional genetics, the link between genetic and epigenetic abnormalities, alteration of the DNA repair pathways, disease-associated immune alterations, and the role of the microenvironment in disease development and evolution.
Recent publications:
- Merlevede J et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nature Communications, 2016, in Press.
- Selimoglu-Buet D et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015 Jun 4;125(23):3618-26
- de Laval B et al. Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1. Blood. 2014;123(4):509-19.
- de Laval B et al. Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage. Cell Stem Cell. 2013;12(1):37-48.
- Itzykson R et al. Clonal architecture of chronic myelomonocytic leukemias. Blood. 2013;121(12):2186-98.
- Saulnier N et al. ERK1 regulates the hematopoietic stem cell niches. PLoS One. 2012;7(1):e30788
- Zhang Y et al. CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model. Cell Death Dis. 2012;3:e396.
