Vav1 in differentiation of tumoral promyelocytes

Bertagnolo, Valeria; Brugnoli, Federica; Grassilli, Silvia; Nika, Ervin; Capitani, Silvano

doi:10.1016/j.cellsig.2011.11.017

Cited by 19 publications

(31 citation statements)

References 103 publications

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“…However if the second treatment was RA, Vav1 expression tended to diminish by 48 h. A similar outcome occurs for c-Cbl, and p47 phox . Thus, although ectopic overexpression of Vav1 or c-Cbl can enhance RA-induced differentiation in WT HL-60 [9], [33], early-induced expression of these signaling factors in resistant cells is not enough to propel RA-induced differentiation during the lineage-commitment stage, which may reflect the co-existence of other potential defects. The data suggest that a late Vav1-dependent function may be disrupted in resistance, and lesser Vav1 expression in R38− compared to R38+ cells may contribute to the increased D 3 resistance in R38− cells.…”

Section: Discussionmentioning

confidence: 99%

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Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

et al. 2014

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Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA) is the standard therapeutic agent for acute promyelocytic leukemia, but 10–20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2) HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17)-negative cells. Wild-type (WT) HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3). Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or “precommitment” phase) or subsequently (the late or “lineage-commitment” phase). HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness (unilineage maturation block), followed by bilineage maturation block and progressive signaling defects, notably the reduced expression of Vav1, Fgr, and c-Raf.

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Section: Discussionmentioning

confidence: 99%

“…Vav1 is required for RA-induced granulocytic differentiation [33] as well as TPA-induced monocytic differentiation of HL-60 [34]. Vav1, along with c-Cbl and Slp76, exhibit increased expression and exist in a CD38-associated complex during RA-induced differentiation of WT HL-60 [9].…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

et al. 2014

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“…Vav1 is the sole of the 3 members of the Vav family to be physiologically expressed exclusively in haematopoietic cells in which, in parallel with the best known function as a guanosine exchange factor (GEF) mainly devoted to the rearrangement of actin cytoskeleton [3], it acts as an adaptor/regulator molecule in both cytoplasm and nuclear compartments [4-6]. Vav1 plays a crucial role in maturation and function of both myeloid and lymphoid cells [6] and its expression in non-hematopoietic tissues, including breast, is associated with a tumoral phenotype [7-12].…”

Section: Introductionmentioning

confidence: 99%

“…Vav1 plays a crucial role in maturation and function of both myeloid and lymphoid cells [6] and its expression in non-hematopoietic tissues, including breast, is associated with a tumoral phenotype [7-12]. Contrarily to other solid tumors, in which Vav1 positively correlates with malignancy [8, 12], the Vav1 transcript in breast cancers seems to be higher in tumors from patients that remained disease free than in patients who developed recurrence [13].…”

Section: Introductionmentioning

confidence: 99%

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High nuclear level of Vav1 is a positive prognostic factor in early invasive breast tumors: a role in modulating genes related to the efficiency of metastatic process

et al. 2014

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Vav1 is one of the signalling proteins normally restricted to hematopoietic cells that results ectopically expressed in solid tumors, including breast cancer. By immunohistochemical analysis on TMAs containing invasive breast tumor from patients without lymph node involvement, we have found that Vav1 is expressed in almost all investigated cancers and shows a peculiar localization inside the nucleus of tumor cells. High amounts of nuclear Vav1 are positively correlated with low incidence of relapse, regardless phenotype and molecular subtype of breast neoplasia. In particular, Kaplan-Meier plots showed an elevated risk of distant metastasis in patients with low Vav1 expression compared with patients with high Vav1 expression in their tumors. Experiments performed with breast tumor-derived cells indicated that Vav1 negatively modulates their invasiveness in vitro and their metastatic efficiency in vivo, possibly by affecting the expression of genes involved in invasion and/or metastasis of breast tumors. Since the high heterogeneity of breast tumors makes difficult to predict the evolution of early breast neoplasias, the evaluation of nuclear Vav1 levels may help in the characterization and management of early breast cancer patients. In particular, Vav1 may serve as a prognostic biomarker and a target for new therapies aimed to prevent breast cancer progression.

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Vav1 downmodulates Akt in different breast cancer subtypes: a new promising chance to improve breast cancer outcome

et al. 2018

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Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p‐Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumor‐derived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER‐negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p‐Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow‐up of patients with low p‐Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple‐negative phenotype, for which target‐based therapies are not currently available.

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Vav1 in differentiation of tumoral promyelocytes

Cited by 19 publications

References 103 publications

Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

Retinoic Acid Therapy Resistance Progresses from Unilineage to Bilineage in HL-60 Leukemic Blasts

High nuclear level of Vav1 is a positive prognostic factor in early invasive breast tumors: a role in modulating genes related to the efficiency of metastatic process

Vav1 downmodulates Akt in different breast cancer subtypes: a new promising chance to improve breast cancer outcome

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