Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO

N, Da Silva; Meyer-Monard, Sandrine; Ml, Menot; Parrado, Antonio; Lebel, Andréa A.; Balitrand, N; Fenaux, Pierre; Jm, Micléa; Rousselot, Philippe; Degos, Laurent; Dombret, Hervé; Chomienne, Christine

doi:10.1038/sj.thj.6200047

Cited by 17 publications

(8 citation statements)

References 47 publications

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“…In response to ligand-binding, surface expression of the mutant G-CSFR forms was found to be increased, which correlated with sustained intracellular activation and enhanced growth and survival responses to G-CSF [10,29,30,36]. Increased expression of the G-CSFR either at the mRNA or protein level has also been reported in patients with AML without antecedent SCN, and in patients with CML and acute and chronic lymphoid leukemias [37][38][39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller

Druhan

et al. 2008

Cytokine

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The granulocyte colony-stimulating factor receptor (G-CSFR) is a critical regulator of granulopoiesis, but the mechanisms controlling its surface expression are poorly understood. Recent studies using transfected cell lines have suggested the activated G-CSFR is routed to the lysosome and not the proteasome. Here, we examined the role of the ubiquitin/proteasome system in regulating G-CSFR surface expression in both ts20 cells that have a temperature-sensitive E1 ubiquitinactivating enzyme and in primary human neutrophils. We show that the G-CSFR is constitutively ubiquitinated, which increases following ligand binding. In the absence of a functional E1 enzyme, ligand-induced internalization of the receptor is inhibited. Pre-treatment of ts20 transfectants with either chloroquine or MG132 inhibited ligand-induced G-CSFR degradation, suggesting a role for both lysosomes and proteasomes in regulating G-CSFR surface expression in this cell line. In neutrophils, inhibition of the proteasome but not the lysosome was found to inhibit internalization/ degradation of the activated G-CSFR. Collectively, these data demonstrate the requirement for a functional ubiquitin/proteasome system in G-CSFR internalization and degradation. Our results suggest a prominent role for the proteasome in physiologic modulation of the G-CSFR, and provide further evidence for the importance of the ubiquitin/proteasome system in the initiation of negative signaling by cytokine receptors.

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Section: Discussionmentioning

confidence: 99%

Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller

Druhan

et al. 2008

Cytokine

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“…On one hand, it has been demonstrated that G-CSF is capable of inducing in vitro and in vivo maturation of t(8;21) AML cells. 38,39 On the other hand, despite the large number of randomized (and generally negative) G-CSF studies reported to date in AML patients, 40 we do not know if there is any interaction between G-CSF therapy and the presence of the t(8;21) translocation.…”

Section: Discussionmentioning

confidence: 99%

A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup

Nguyen

2002

Blood

163

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While the t(8;21) translocation is one of the most recurrent chromosomal abnormalities in acute myeloid leukemia, prognostic studies have been hampered by the relatively few number of patients reported. We thus performed a large retrospective study in 161 adults and children with t(8;21) acute myeloid leukemia, all prospectively enrolled in 6 different trials conducted in France between 1987 and 1998 (median follow-up 4.9 years). Prognostic studies were performed in the 154 patients who achieved a complete remission. Individual data were registered, including sex, age, blood and marrow counts, extramedullary disease, and cytogenetics. The value of allogeneic stem cell transplantation versus chemotherapy as postremission therapy was evaluated according to the intent-to-treat principle. Estimated 5-year disease-free survival (DFS) and overall survival were 52% and 59%, respectively. Outcome was not significantly better in patients from the stem cell transplantation group (estimated 5-year DFS and survival, 56% vs 52% and 67% vs 57%; P ‫؍‬ .55 and .64, respectively). White blood cell count (WBC) was the only identified prognostic factor. To further take into account the spontaneous differentiation potential of the leukemic clone, a WBC index was derived as the product of WBC by the ratio of marrow blast. This WBC index was a more powerful factor than the original WBC, allowing us to distinguish 3 subgroups of patients with different outcomes (low index, < 2.5; intermediate index, 2.5-20; high index, 20 or more). In multivariate analysis, the WBC index was the only prognostic factor for DFS (P ‫؍‬ .003), complete remission duration (P ‫؍‬ .002), and overall survival (P ‫؍‬ .04). (Blood. 2002;99:3517-3523)

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“…These up-regulations are rapid and transcriptionally regulated, whereas subsequent decrease of RARa or PML ± RARa are post-transcriptional and related to proteasome degradation (Zhu et al, 1999), as also noted after dierentiation of APL cells via CD44 activation (Charrad et al, 1999) or for other hematopoietic oncogenes or transcriptional proteins such as AML 1 ± ETO or ETO (Da Silva et al, 2000) once dierentiation is achieved. Most other RA-target genes, such as C/EBPe (Morosetti et al, 1997) have been studied in cell lines, but have not to date been reported on fresh APL cells (Altucci et al, 2001).…”

Section: Retinoic Acid Signaling Pathways In Apl Cellsmentioning

confidence: 99%

Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management

Cassinat

Chomienne

2001

Oncogene

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In recent years, discovery of the in vitro and in vivo dierentiation of APL blasts by all-trans retinoic acid (ATRA) has modi®ed the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that dierentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid ecacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic de®nition of the leukemia, others have just been de®ned or re-discovered in the light of a better understanding of molecular controls of cell growth and dierentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identi®ca-tion of potential markers for dierentiation therapies in other leukemias or solid tumors. Oncogene (2001) 20, 7154 ± 7160.

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Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO

Abstract: The data presented here supports the claim that G-CSF can induce in vitro and in vivo differentiation of M2 AML t(8;21) cells.

Cited by 17 publications

References 47 publications

Role of the proteasome in modulating native G-CSFR expression

Role of the proteasome in modulating native G-CSFR expression

A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup

Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management

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