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Emmanuelle Passegué

Publications and source records attributed to Emmanuelle Passegué.

16 recordsLinked to original sources
PubMed2006

K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells.

Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-Ras(G12D) expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.

Animals↗
PubMed2006

Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.

The targeted inactivation of oncogenes offers a rational therapeutic approach for the treatment of cancer. However, the therapeutic inactivation of a single oncogene has been associated with tumor recurrence. Therefore, it is necessary to develop strategies to override mechanisms of tumor escape from oncogene dependence. We report here that the targeted inactivation of MYC is sufficient to induce sustained regression of hematopoietic tumors in transgenic mice, except in tumors that had lost p53 function. p53 negative tumors were unable to be completely eliminated, as demonstrated by the kinetics of tumor cell elimination revealed by bioluminescence imaging. Histological examination revealed that upon MYC inactivation, the loss of p53 led to a deficiency in thrombospondin-1 (TSP-1) expression, a potent antiangiogenic protein, and the subsequent inability to shut off angiogenesis. Restoration of p53 expression in these tumors re-established TSP-1 expression. This permitted the suppression of angiogenesis and subsequent sustained tumor regression upon MYC inactivation. Similarly, the restoration of TSP-1 alone in p53 negative tumors resulted in the shut down of angiogenesis and led to sustained tumor regression upon MYC inactivation. Hence, the complete regression of tumor mass driven by inactivation of the MYC oncogene requires the p53-dependent induction of TSP-1 and the shut down of angiogenesis. Notably, overexpression of TSP-1 alone did not influence tumor growth. Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction.

Animals↗
PubMed2006

Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells.

Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1-knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.

Animals↗
PubMed2006

New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors.

A model of hematopoietic development wherein multipotentiality is conserved until segregation of myeloid and lymphoid potential has recently been challenged, proposing that megakaryocyte/erythrocyte (MegE) potential is lost in Flk2/Flt3-expressing early progenitors. Here, we used sensitive in vivo approaches to quantitatively and kinetically assess the MegE potential of hematopoietic stem cells and various Flk2(+) early progenitors and compared it with the MegE potential of downstream committed myeloid and lymphoid progenitors and with their ability to give rise to mature myelomonocytic and lymphoid cells. We demonstrate that Flk2(+) early progenitors retain MegE potential in vivo both at the population and clonal levels. These results indicate that Flk2 expression by early progenitors is not at the expense of full multipotency and support the current model of hematopoietic development with segregation of myeloid and lymphoid lineages from multipotent progenitors.

Animals↗
PubMed2006

Regulating quiescence: new insights into hematopoietic stem cell biology.

Blood-forming hematopoietic stem cells (HSCs) ensure production of all mature blood cells during homeostatic and regenerative hematopoiesis. Proliferation, cell cycle regulation, and quiescence are key processes involved in this function, and in a recent issue of Cancer Cell, show that HSC quiescence is actively regulated by specific molecular mechanisms that appear to distinguish normal HSC maintenance from HSC responses to hematologic injury.

Animals↗
PubMed2005

Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates.

Knowledge of the molecular networks controlling the proliferation and fate of hematopoietic stem cells (HSC) is essential to understand their function in maintaining blood cell production during normal hematopoiesis and upon clinical transplantation. Using highly purified stem and progenitor cell populations, we define the proliferation index and status of the cell cycle machinery at discrete stages of hematopoietic differentiation and during cytokine-mediated HSC mobilization. We identify distinct sets of cell cycle proteins that specifically associate with differentiation, self-renewal, and maintenance of quiescence in HSC and progenitor cells. Moreover, we describe a striking inequality of function among in vivo cycling and quiescent HSC by demonstrating that their long-term engraftment potential resides predominantly in the G(0) fraction. These data provide a direct link between HSC proliferation and function and identify discrete molecular targets in regulating HSC cell fate decisions that could have implications for both the therapeutic use of HSC and the understanding of leukemic transformation.

Animals↗
PubMed2005

Hematopoietic stem cells, leukemic stem cells and chronic myelogenous leukemia.

Blood-related cancers, or leukemias, have been shown to arise from a rare subset of cells that escape normal regulation and drive the formation and growth of the tumor. The finding that these so-called cancer stem cells, or leukemic stem cells (LSC), can be purified away from the other cells in the tumor allows their precise analysis to identify candidate molecules and regulatory pathways that play a role in progression, maintenance, and spreading of leukemias. The analyses of the other, numerically dominant, cells in the tumor, while also interesting, do not directly interrogate these key properties of malignancies. Mouse models of human myeloproliferative disorder and acute myelogenous leukemia have highlighted the remarkable conservation of disease mechanisms between both species. They can now be used to identify the LSC for each type of human leukemia and understand how they escape normal regulation and become malignant. Given the clinical importance of LSC identification, the insights gained through these approaches will quickly translate into clinical applications and lead to improved treatments for human leukemias.

Animals↗
PubMed2005

Leukemic stem cells: where do they come from?

Leukemias can now be viewed as aberrant hematopoietic processes initiated by rare cancer stem cells, or leukemic stem cells (LSCs) that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSCs and the mechanisms responsible for their emergence in the course of the disease. Mouse models of human leukemias have provided a unique system to study the mechanisms influencing LSC generation and function, and were recently used to demonstrate that LSCs can arise from both self-renewing hematopoietic stem cells (HSCs) and committed progenitor populations. This striking finding indicates that LSC identity is largely dictated by the nature of the oncogenic events and by how these events perturb essential processes such as self-renewal, proliferation, differentiation, and survival. Such approaches in the mouse are essential for the basic understanding of leukemogenesis and for the conceptual design of novel therapeutic strategies that could lead to improved treatments for human leukemias.

Animals↗
PubMed2004

JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells.

The AP-1 transcription factor JunB is a transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.

Animals↗
PubMed2004

Chronic versus acute myelogenous leukemia: a question of self-renewal.

Leukemia stem cells are defined as transformed hematopoietic stem cells or committed progenitor cells that have amplified or acquired the stem cell capacity for self-renewal, albeit in a poorly regulated fashion. In this issue of Cancer Cell, Huntly and colleagues report a striking difference in the ability of two leukemia-associated fusion proteins, MOZ-TIF2 and BCR-ABL, to transform myeloid progenitor populations. This rigorous study supports the idea of a hierarchy among leukemia-associated protooncogenes for their ability to endow committed myeloid progenitors with the self-renewal capacity driving leukemic stem cell propagation, and sheds new light on the pathogenesis of chronic and acute myelogenous leukemias.

Acute Disease↗
PubMed2003

Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors.

We have used the hematopoietic system as a model to investigate whether acute myeloid leukemia arises exclusively from self-renewing stem cells or also from short-lived myeloid progenitors. When transduced with a leukemogenic MLL fusion gene, prospectively isolated stem cells and myeloid progenitor populations with granulocyte/macrophage differentiation potential are efficiently immortalized in vitro and result in the rapid onset of acute myeloid leukemia with similar latencies following transplantation in vivo. Regardless of initiating cell, leukemias displayed immunophenotypes and gene expression profiles characteristic of maturation arrest at an identical late stage of myelomonocytic differentiation, putatively a monopotent monocytic progenitor stage. Our findings unequivocally establish the ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene, and support the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin.

Acute Disease↗
PubMed2003

Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?

Leukemia can be viewed as a newly formed, abnormal hematopoietic tissue initiated by a few leukemic stem cells (LSCs) that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal hematopoietic stem cells. A hallmark of all cancers is the capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells. Given this shared attribute, it has been proposed that leukemias may be initiated by transforming events that take place in hematopoietic stem cells. Alternatively, leukemias may also arise from more committed progenitors caused by mutations and/or selective expression of genes that enhance their otherwise limited self-renewal capabilities. Identifying the LSCs for each type of leukemia is a current challenge and a critical step in understanding their respective biologies and may provide key insights into more effective treatments. Moreover, LSC identification and purification will provide a powerful diagnostic, prognostic, and therapeutic tool in the clinic.

Animals↗
PubMed2003

JunB inhibits proliferation and transformation in B-lymphoid cells.

The activator protein 1 (AP-1) member JunB has recently been implicated in leukemogenesis. Here we surveyed human lymphoma samples for expression of JunB and other AP-1 members (c-Jun, c-Fos, Fra1, JunD). JunB was strongly expressed in T-cell lymphomas, but non-Hodgkin B-cell lymphomas do not or only weakly express JunB. We therefore asked whether JunB acted as a negative regulator of B-cell development, proliferation, and transformation. We used transgenic mice that expressed JunB under the control of the ubiquitin C promoter; these displayed increased JunB levels in both B- and T-lymphoid cells. JunB transgenic cells of B-lymphoid, but not of T-lymphoid, origin responded poorly to mitogenic stimuli. Furthermore, JunB transgenic cells were found to be less susceptible to the transforming potential of the Abelson oncogene in vitro. In addition, overexpression of JunB partially protected transgenic mice against the oncogenic challenge in vivo. However, transformed B cells eventually escaped from the inhibitory effect of JunB: the proliferative response was similar in explanted tumor-derived cells from transgenic animals and those from wild-type controls. Our results identify JunB as a novel regulator of B-cell proliferation and transformation.

Animals↗
PubMed2003

MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice.

A specific association with mixed lineage leukemias suggests that MLL oncoproteins may selectively target early multipotent hematopoietic progenitors or stem cells. We demonstrate here that a representative MLL fusion protein, MLL-GAS7, impairs the differentiation and enhances the in vitro growth of murine hematopoietic cells with multipotent features. The multilineage differentiation potential of these cells was suggested by their immuno-phenotypes and transcriptional programs and confirmed by their ability to induce three pathologically distinct leukemias in mice, including an acute biphenotypic leukemia (ABL) that recapitulates the distinctive hallmark features of many MLL-associated leukemias in humans. This experimental modeling of ABL in mice highlights its origin from multipotential progenitors that arrest at a bipotential stage specifically targeted or induced by MLL oncogenes.

Animals↗
PubMed2002

JunB can substitute for Jun in mouse development and cell proliferation.

The Jun and JunB components of the AP-1 transcription factor are known to have antagonistic functions. Here we show, by a knock-in strategy and a transgenic complementation approach, that Junb can substitute for absence of Jun during mouse development. Junb can rescue both liver and cardiac defects in Jun-null mice in a manner dependent on gene dosage. JunB restores the expression of genes regulated by Jun/Fos, but not those regulated by Jun/ATF, thereby rescuing Jun-dependent defects in vivo as well as in primary fibroblasts and fetal hepatoblasts in vitro. Thus, the transcriptionally less active JunB has the potential to substitute for Jun, indicating that the spatial and temporal regulation of expression of the transcription factor AP-1 may be more important than the coding sequence of its components.

Animals↗