Pim2 cooperates with PML-RARα to induce acute myeloid leukemia in a bone marrow transplantation model

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4507-4516 ◽  
Author(s):  
Shuchi Agrawal-Singh ◽  
Steffen Koschmieder ◽  
Sandra Gelsing ◽  
Carol Stocking ◽  
Martin Stehling ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Immature Myeloid Cells ◽  
Retinoic Acid Receptor Α ◽  
Transplantation Model

Abstract Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with promyelocytic leukemia/retinoic acid receptor α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon all-trans retinoic acid (ATRA) treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RARα), cooperates with PRα to induce APL-like disease.

Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto

2001 ◽  
Vol 19 (20) ◽  
pp. 4023-4028 ◽  
Author(s):  
Giorgina Specchia ◽  
Francesco Lo Coco ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Paola Fazi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Increased Risk ◽  
Junction Type ◽  
Wbc Count

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

scholarly journals CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2416-2419 ◽  
Author(s):  
Young-Jin Lee ◽  
Letetia C. Jones ◽  
Nikolai A. Timchenko ◽  
Danilo Perrotti ◽  
Daniel G. Tenen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Binding Proteins ◽  
Retinoic Acid Receptor ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Enhancer Binding Proteins ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Receptor Α

Abstract CCAAT/enhancer binding proteins (C/EBPs) play critical roles in myelopoiesis. Dysregulation of these proteins likely contributes to the pathogenesis of myeloid disorders characterized by a block in granulopoiesis. In one such disease, acute promyelocytic leukemia (APL), a promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion protein is expressed as a result of a t(15;17) chromosomal translocation. Treatment of PML-RARα leukemic cells with all-trans retinoic acid (ATRA) causes them to differentiate into mature neutrophils, an effect thought to be mediated by C/EBPs. In this study, we assess the potential for cooperativity between increased C/EBP activity and ATRA therapy. We demonstrate that although both C/EBPα and C/EBPϵ can significantly prolong survival in a mouse model of APL, they are not functionally equivalent in this capacity. We also show that forced expression of C/EBPα or C/EBPϵ in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared with either therapy alone.

Regulation of S100A10 by the PML-RAR-α oncoprotein

Blood ◽  
2011 ◽  
Vol 117 (15) ◽  
pp. 4095-4105 ◽  
Author(s):  
Paul A. O'Connell ◽  
Patricia A. Madureira ◽  
Jason N. Berman ◽  
Robert S. Liwski ◽  
David M. Waisman
Keyword(s):  
Retinoic Acid ◽  
Cell Surface ◽  
Fibrinolytic Activity ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Receptor Α ◽  
First Time ◽  
Distinct Subtype

Abstract Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia that results from the expression of the promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) oncoprotein. It is characterized by severe hemorrhagic complications due in part to excessive fibrinolysis, resulting from the excessive generation of the fibrinolytic enzyme, plasmin, at the cell surface of the PML cells. The treatment of patients with all-trans retinoic acid (ATRA) effectively ameliorates the disease by promoting the destruction of the PML-RAR-α oncoprotein. In the present study we show for the first time that the plasminogen receptor, S100A10, is present on the extracellular surface of APL cells and is rapidly down-regulated in response to all-trans retinoic acid. The loss of S100A10 is concomitant with a loss in fibrinolytic activity. Furthermore, the induced expression of the PML-RAR-α oncoprotein increased the expression of cell surface S100A10 and also caused a dramatic increase in fibrinolytic activity. Depletion of S100A10 by RNA interference effectively blocked the enhanced fibrinolytic activity observed after induction of the PML-RAR-α oncoprotein. These experiments show that S100A10 plays a crucial role in the generation of plasmin leading to fibrinolysis, thus providing a link to the clinical hemorrhagic phenotype of APL.

Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5289-5297 ◽  
Author(s):  
Zhi-Min Gu ◽  
Ying-Li Wu ◽  
Mei-Yi Zhou ◽  
Chuan-Xu Liu ◽  
Han-Zhang Xu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Natural Ligand ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Induction Of Differentiation ◽  
Retinoic Acid Receptor Α

Abstract All-trans retinoic acid (ATRA), a natural ligand for the retinoic acid receptors (RARs), induces clinical remission in most acute promyelocytic leukemia (APL) patients through the induction of differentiation and/or eradication of leukemia-initiating cells. Here, we identify a novel natural ent-kaurene diterpenoid derived from Isodon pharicus leaves, called pharicin B, that can rapidly stabilize RAR-α protein in various acute myeloid leukemic (AML) cell lines and primary leukemic cells from AML patients, even in the presence of ATRA, which is known to induce the loss of RAR-α protein. Pharicin B also enhances ATRA-dependent the transcriptional activity of RAR-α protein in the promyelocytic leukemia–RARα–positive APL cell line NB4 cells. We also showed that pharicin B presents a synergistic or additive differentiation-enhancing effect when used in combination with ATRA in several AML cell lines and, especially, some primary leukemic cells from APL patients. In addition, pharicin B can overcome retinoid resistance in 2 of 3 NB4-derived ATRA-resistant subclones. These findings provide a good example for chemical biology–based investigations of pathophysiological and therapeutic significances of RAR-α and PML-RAR-α proteins. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients.

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2324-2331 ◽  
Author(s):  
Pauline Isakson ◽  
Magnar Bjørås ◽  
Stig Ove Bøe ◽  
Anne Simonsen
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Retinoic Acid Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Degradation Pathway ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
The Stability

Abstract Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide represents a paradigm in targeted cancer therapy because these drugs cause clinical remission by affecting the stability of the fusion oncoprotein promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARA). The authors of previous studies have implicated the ubiquitin-proteasome pathway as the main mechanism involved in therapy-induced PML/RARA degradation. Here we have investigated a role of autophagy, a protein degradation pathway that involves proteolysis of intracellular material within lysosomes. We found that both all-trans retinoic acid and arsenic trioxide induce autophagy via the mammalian target of rapamycin pathway in APL cells and that autophagic degradation contributes significantly both to the basal turnover as well as the therapy-induced proteolysis of PML/RARA. In addition, we observed a correlation between autophagy and therapy-induced differentiation of APL cells. Given the central role of the PML/RARA oncoprotein in APL pathogenesis, this study highlights an important role of autophagy in the development and treatment of this disease.

scholarly journals Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 46028-46041 ◽  
Author(s):  
Farzaneh Atashrazm ◽  
Ray M. Lowenthal ◽  
Joanne L. Dickinson ◽  
Adele F. Holloway ◽  
Gregory M. Woods
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Therapeutic Potential ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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