ATRA Therapy in Acute Promyelocytic Leukemia a Model for Differentiation Therapy

1993 ◽  
pp. 99-108
Author(s):  
Laurent Degos
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Differentiation Therapy

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

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5512-5521 ◽  
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.

Deregulation of RARγ and RARγ-Specific miRNAs in AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3182-3182
Author(s):  
Angela N. Barrett ◽  
Rajeev Gupta ◽  
Annegret Glasow ◽  
David Grimwade ◽  
Marieke von Lindern ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cord Blood ◽  
Acute Promyelocytic Leukemia ◽  
Cell Lines ◽  
Promyelocytic Leukemia ◽  
Differentiation Therapy ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Myeloid Progenitors

Abstract All-trans-retinoic acid (ATRA) plays important regulatory roles in hematopoiesis and is successfully used in differentiation therapy of acute promyelocytic leukemia (APL). Although ATRA effectively inhibits growth and stimulates myelomonocytic differentiation of myeloid progenitors, it is equally potent in causing expansion of multipotent hematopoietic stem cells. Results of studies utilizing mice that lack expression of a specific RAR and/or RAR subtype specific retinoids, as well as work addressing the molecular pathogenesis of acute promyelocytic leukemia (APL), indicate that the effects of ATRA on hematopoietic stem cells and myeloid progenitors are differentially mediated via the RARγ and RARα, respectively. Using qPCR we have now shown that RARγ is expressed in human cord blood derived stem cells but not in more mature myeloid progenitors or myelomonocytic cells. This change in the RARγ expression levels is paralleled by a reciprocal change in expression of RARγ specific miRNA, which we have identified and validated using multiple experimental strategies, including RARγ 3′UTR based reporter assays. RARγ is also expressed in blasts derived from non-APL AML patients (over 80% of cases examined) and AML cell lines, but is not expressed in ATRA responsive APL cell lines. The expression of RARγ miRNA, on the other hand, is markedly decreased in AML blasts when compared to the levels detected in cord blood derived CD34+ myeloid progenitor cells. Taken together our results suggest that finely tuned and miRNA mediated down-regulation of RARγ expression in the myelomonocytic lineage provides a switch from pro-proliferation to RARα mediated pro-differentiation effects of ATRA. We predict that use of a RARα specific agonist, possibly in conjunction with a strategy that negatively targets RARγ (as with RARγ selective antagonist or siRNA), would be most effective in retinoid based differentiation therapy of non APL-AML.

Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia

2018 ◽  
Vol 108 (3) ◽  
pp. 274-281 ◽  
Author(s):  
Kazuyuki Sato ◽  
Hirotaka Sakai ◽  
Yusuke Saiki ◽  
Akiko Uchida ◽  
Yu Uemura ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Differentiation Therapy ◽  
Cell Dynamics ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Differentiation Therapy of Acute Promyelocytic Leukemia with Tretinoin (All-trans-Retinoic Acid)

1991 ◽  
Vol 324 (20) ◽  
pp. 1385-1393 ◽  
Author(s):  
Raymond P. Warrell ◽  
Stanley R. Frankel ◽  
Wilson H. Miller ◽  
David A. Scheinberg ◽  
Loretta M. Itri ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Differentiation Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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