PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity

Noguera, Nélida I.; Piredda, Maria Liliana; Taulli, Riccardo; Catalano, Gianfranco; Angelini, Giulia; Gaur, Girish; Nervi, Clara; Voso, Maria Teresa; Lunardi, Andrea; Pandolfi, Pier Paolo

doi:10.18632/oncotarget.11964

Cited by 22 publications

(20 citation statements)

References 36 publications

(49 reference statements)

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“…U937-PR9 and Mock control cells were prepared using a cytocentrifuge. Assays were performed as previously described [35]. Briefly, cells fixed with 4% paraformaldehyde (PFA) were permeabilized in PBS containing 0.1% Nonidet P-40 and blocked in 3% bovine serum albumin (BSA) (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Immunofluorescence Assaysmentioning

confidence: 99%

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

Banella

Catalano

Travaglini

et al. 2019

Cancers

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NRF2 (NF-E2 p45-related factor 2) orchestrates cellular adaptive responses to stress. Its quantity and subcellular location is controlled through a complex network and its activity increases during redox perturbation, inflammation, growth factor stimulation, and energy fluxes. Even before all-trans retinoic acid (ATRA) treatment era it was a common experience that acute promyelocytic leukemia (APL) cells are highly sensitive to first line chemotherapy. Since we demonstrated how high doses of ascorbate (ASC) preferentially kill leukemic blast cells from APL patients, we aimed to define the underlying mechanism and found that promyelocytic leukemia/retinoic acid receptor α (PML/RARa) inhibits NRF2 function, impedes its transfer to the nucleus and enhances its degradation in the cytoplasm. Such loss of NRF2 function alters cell metabolism, demarcating APL tissue from both normal promyelocytes and other acute myeloide leukemia (AML) blast cells. Resistance to ATRA/arsenic trioxide (ATO) treatment is rare but grave and the metabolically-oriented treatment with high doses of ASC, which is highly effective on APL cells and harmless on normal hematopoietic stem cells (HSCs), could be of use in preventing clonal evolution and in rescuing APL-resistant patients.

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Section: Immunofluorescence Assaysmentioning

confidence: 99%

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

Banella

Catalano

Travaglini

et al. 2019

Cancers

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“…These data are consistent with the overall rarity of hematological malignancy amongst individuals with chronic inflammatory phenotypes, despite the relative increase in risk (Anderson et al, 2009;Ganan-Gomez et al, 2015). On the other hand, loss-of function mutations in PU.1 itself are rarely observed in hematological malignancy, though a wide array of myeloid leukemia-associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, and mitogenic kinase mutations in BCR/ABL and Flt3 ITD (Gerloff et al, 2015;McKenzie et al, 2019;Mueller et al, 2006;Noguera et al, 2016;Vangala et al, 2003;Yang et al, 2012). In addition, TET2 and/or DNMT3A mutations associated with early oncogenesis may interfere with PU.1 function due to aberrant methylation of PU.1 binding sites (Kaasinen et al, 2019).…”

Section: Discussionmentioning

confidence: 58%

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Rabe

Loeffler

Higa

et al. 2020

Preprint

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Loss of hematopoietic stem cell (HSC) quiescence and resulting clonal expansion are common initiating events in the development of hematological malignancy. Likewise, chronic inflammation related to aging, disease and/or tissue damage is associated with leukemia progression, though its role in oncogenesis is not clearly defined. Here, we show that PU.1-dependent repression of protein synthesis and cell cycle genes in HSC enforces homeostatic protein synthesis levels and HSC quiescence in response to IL-1 stimulation. These genes are constitutively de-repressed in PU.1-deficient HSC, leading to activation of protein synthesis, loss of quiescence and aberrant expansion of HSC. Taken together, our data identify a mechanism whereby HSC regulate their cell cycle activity and pool size in response to chronic inflammatory stress.

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“…All-trans retinoic acids (ATRA), decitabine, ZnSO 4 and Arsenic trioxide (all from Sigma-Aldrich, Steinheim, Germany), were dissolved in DMSO (10 mM stock solution, SS), Acetic Acid 50% (10mM SS), water (1M SS) and PBS (1x), respectively. DAC was added to the culture medium at 1 μM for 3 days, whereas ATO and ATRA were added to the culture medium at 1 μM for 1 day, as previously reported [ 3 , 23 ]. ZnSO 4 was added to the culture medium at 100 μM for 1 day [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

“…DAC was added to the culture medium at 1 μM for 3 days, whereas ATO and ATRA were added to the culture medium at 1 μM for 1 day, as previously reported [ 3 , 23 ]. ZnSO 4 was added to the culture medium at 100 μM for 1 day [ 3 ]. Acetic Acid 50% and DMSO were used as control.…”

Section: Methodsmentioning

confidence: 99%

The forkhead box C1 (FOXC1) transcription factor is downregulated in acute promyelocytic leukemia

et al. 2017

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Forkhead box (FOX) genes encode transcription factors, which regulate embryogenesis and play an important role in hematopoietic differentiation and in mesenchymal niche maintenance. Overexpression of the family member FOXC1 has been reported in solid tumors and acute myeloid leukemia (AML).We studied FOXC1 expression and function in acute promyelocytic leukemia (APL) and normal hematopoietic progenitors. FOXC1 mRNA and protein levels were significantly lower in primary marrow samples from 27 APL patients, as compared to samples obtained from 27 patients with other AML subtypes, and 5 normal CD34+ hematopoietic cells. FOXC1 expression significantly increased in APL samples at the time of remission following consolidation treatment. In cell lines overexpressing PML-RARA, and in the NB4 t(15;17)-positive cell line, FOXC1 expression was lower than in other non-APL cell lines, and increased following treatment with all-trans retinoic acid (ATRA), due to functional binding of ATRA to the FOXC1 promoter region. Reduced FOXC1 expression was also associated to DNA hypermethylation of the +354 to +568 FOXC1 region, both in primary APL, and in NB4 cells. Treatment of NB4 cells with decitabine demethylated FOXC1 and upregulated its expression.Our findings indicate that FOXC1 is consistently repressed in APL due to hypermethylation and the presence of the PML-RARA rearrangement. A potential role of hypomethylating treatment in advanced APL remains to be established.

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PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity

Cited by 22 publications

References 36 publications

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

The forkhead box C1 (FOXC1) transcription factor is downregulated in acute promyelocytic leukemia

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