Expression of RXRa in Human Leukemic Cells During Differentiation Induced by All-Trans Retinoic Acid and 1a,25-Dihydroxyvitamin D

AbstractEcotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

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Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells [see comments]

Blood ◽

10.1182/blood.v82.7.2175.2175 ◽

1993 ◽

Vol 82 (7) ◽

pp. 2175-2181 ◽

Cited By ~ 127

Author(s):

L Delva ◽

M Cornic ◽

N Balitrand ◽

F Guidez ◽

JM Miclea ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Binding Protein ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Differentiation Induction ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with “virgin”-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

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Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

Blood ◽

10.1182/blood-2009-02-204834 ◽

2009 ◽

Vol 114 (27) ◽

pp. 5512-5521 ◽

Cited By ~ 57

Author(s):

Maaike Luesink ◽

Jeroen L. A. Pennings ◽

Willemijn M. Wissink ◽

Peter C. M. Linssen ◽

Petra Muus ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Differentiation Therapy ◽

Chemokine Production ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Pulmonary Infiltration

Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

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Cooperative Action of 1alpha,25-Dihydroxyvitamin D3 and Retinoic Acid in NB4 Acute Promyelocytic Leukemia Cell Differentiation Is Transcriptionally Controlled.

Blood ◽

10.1182/blood.v106.11.4247.4247 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4247-4247

Author(s):

Jean-Noel Bastie ◽

Nicole Balitrand ◽

Isabelle Guillemot ◽

Christine Chomienne ◽

Laurent Delva

Keyword(s):

Retinoic Acid ◽

Transcriptional Activity ◽

Target Genes ◽

Leukemia Cell ◽

Leukemic Cells ◽

Dihydroxyvitamin D3 ◽

Nb4 Cells ◽

Cooperative Action ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract All-trans-retinoic acid (RA) and 1alpha,25-dihydroxyvitamin D3 (1,25D3) are involved in the control of hematopoiesis and have been suggested to play a role in cellular differentiation and are as such potent inducers of differentiation of myeloid leukemia cells. In this study, we have shown that in promyelocytic NB4 cells, addition of 1,25D3 enhances terminal granulocytic RA-dependent differentiation concomitant with the enhanced activation of the RA-transcriptional activity through an RARbeta promoter. By EMSA and ChIP assays, we further demonstrate that while both VDR and RAR are bound to the RARbeta promoter in NB4 cells, addition of 1,25D3 increases VDR binding to this promoter while that of RA induces the release of VDR and increases the binding of RAR. Thus, contrary to normal myeloid cells, 1,25D3 does not act as a transrepressor of RA-transcriptional activity in leukemic cells suggesting that transcriptional regulation of RA-target genes may be modified in malignant cells. In promyelocytic leukemic cells the combination of 1,25D3 and RA results in both enhanced transactivation and differentiation.

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Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells

Archives of Toxicology ◽

10.1007/s00204-016-1878-5 ◽

2016 ◽

Vol 91 (5) ◽

pp. 2191-2208 ◽

Cited By ~ 15

Author(s):

Katrin Noack ◽

Nisintha Mahendrarajah ◽

Dorle Hennig ◽

Luisa Schmidt ◽

Florian Grebien ◽

...

Keyword(s):

Retinoic Acid ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Leukemic Cells ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Do High-mobility Group Box 1 Gene Polymorphisms Affect the Incidence of Differentiation Syndrome in Acute Promyelocytic Leukemia?

10.21203/rs.3.rs-1084766/v1 ◽

2021 ◽

Author(s):

Ghazaleh Hoseinzadeh ◽

Zahra Mohammadzadeh ◽

Bahram Chahardouli ◽

Kamran Ali Moghaddam ◽

Seyed Asadollah Mousavi ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

High Mobility ◽

Promyelocytic Leukemia ◽

High Mobility Group ◽

Leukemic Cells ◽

Genotype Distribution ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Differentiation syndrome (DS) is an inflammatory complication seen in some patients with acute promyelocytic leukemia (APL) undergoing differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). It is unknown how DS occurs, but it is believed that it is caused by inflammatory cytokines release from differentiating leukemic cells. High mobility group box-1 (HMGB1) is a DNA-binding protein that acts as a cytokine outside of cells and may play a role in inflammation. This study was conducted to determine whether HMGB1 polymorphisms (rs1360485, rs2249825 and rs1060348) are associated with the incidence of differentiation syndrome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic trioxide. One hundred and thirty APL patients and 100 healthy controls were included. Seventeen patients with differentiation syndrome were selected according to the PETHEMA criteria. Tetra-primer ARMS polymerase chain reaction (tetra-ARMS PCR) was used to determine the genotype distribution of polymorphisms. DNA sequencing was done to validate the results. In both healthy and APL patients, AA was the most frequent genotype in rs1360485 followed by AG and GG. CC, CG, and GG were the most frequent genotypes in rs2249825 polymorphism in the order mentioned. CC was more frequent than CT, and CT was more frequent than TT in rs1060348. There was no correlation between HMGB1 polymorphisms and the incidence of differentiation syndrome based on genetic models (p-value > 0.05). As a result, HMGB1 polymorphisms are not probably associated with DS development in APL patients treated with ATRA and ATO.

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Complete Remission of t(11;17) Positive Acute Promyelocytic Leukemia Induced by All-trans Retinoic Acid and Granulocyte Colony-Stimulating Factor

Blood ◽

10.1182/blood.v94.1.39.413a26_39_45 ◽

1999 ◽

Vol 94 (1) ◽

pp. 39-45 ◽

Cited By ~ 61

Author(s):

J.H. Jansen ◽

M.C. de Ridder ◽

W.M.C. Geertsma ◽

C.A.J. Erpelinck ◽

K. van Lom ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Stimulating Factor

The combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted differentiation-based therapy in leukemia. Unfortunately, similar approaches have failed in other types of hematological malignancies suggesting that the applicability is limited to this specific subgroup of patients. This has been endorsed by the notorious lack of response in acute promyelocytic leukemia bearing the variant t(11;17) translocation. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF), we studied maturation of t(11;17) positive leukemia cells using several combinations of retinoic acid and growth factors. In cultures with retinoic acid or G-CSF the leukemic cells did not differentiate into mature granulocytes, but striking granulocytic differentiation occurred with the combination of both agents. At relapse, the patient was treated with retinoic acid and G-CSF before reinduction chemotherapy. With retinoic acid and G-CSF treatment alone, complete granulocytic maturation of the leukemic cells occurred in vivo, followed by a complete cytogenetical and hematological remission. Bone marrow and blood became negative in fluorescense in situ hybridization analysis and semi-quantitative polymerase chain reaction showed a profound reduction of promyelocytic leukemia zinc finger–retinoic acid receptor- fusion transcripts. This shows that t(11;17) positive leukemia cells are not intrinsically resistant to retinoic acid, provided that the proper costimulus is administered. These observations may encourage the investigation of combinations of all-trans retinoic acid and hematopoietic growth factors in other types of leukemia.

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