Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia

Lo‐Coco, Francesco; Avvisati, Giuseppe; Vignetti, Marco; Thiede, Christian; Iacobelli, Simona; Ferrara, Felicetto; Fazi, Paola; Cicconi, Laura; Bona, Eros Di; Specchia, Giorgina; Sica, Simona; Divona, Mariadomenica; Levis, Alessandro; Fiedler, Walter; Cerqui, Elisa; Breccia, Massimo; Fioritoni, Giuseppe; Cazzola, Mario; Melillo, Lorella; Morra, Enrica; Hertenstein, Bernd; Wattad, Mohammed; Lübbert, Michael; Hänel, Mathias; Schmitz, Norbert; Rambaldi, Alessandro; Nasa, Giorgio La; Luppi, Mario; Ciceri, Fabio; Finizio, Olimpia; Venditti, Adriano; Fanfani, Francesco; Döhner, Konstanze; Sauer, Maik; Ganser, Arnold; Amadori, Sergio; Mandelli, Franco; Döhner, Hartmut; Ehninger, Gerhard

doi:10.1056/nejmoa1300874

Cited by 1,290 publications

(1,053 citation statements)

References 38 publications

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“…As frontline treatment, ATO combined with ATRA is as effective as the combinational therapy of ATRA and chemotherapy [5,31]. At high doses, promyelocytes undergo apoptosis in response to ATO.…”

Section: Thiol Redox Inhibitorsmentioning

confidence: 99%

Targeting the mitochondria in acute myeloid leukemia

Sánchez-Mendoza

Rego

2017

Appl Cancer Res

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Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by heterogeneity of genetic abnormalities found at diagnosis. These abnormalities serve to classify patients by risk group into low, intermediate, and high risk. It also provides specific targets for the development of new combinational therapies. However, because of the heterogeneity of genetic abnormalities, targeted therapy is not always possible. Altered mitochondrial metabolism is a common feature in cancer cells, a phenomenon first described by Otto Warburg. In AML patients, the discovery of mutations in the isocitrate dehydrogenase gene provided for the first time a link between altered mitochondrial metabolism and AML. This raised the possibility of testing drugs known as mitocans for new combinational therapeutic approaches. Mitocans are a diverse group of anti-cancer compounds that target mitochondria. They disrupt energy production leading to enhanced generation of reactive oxygen species along with the activation of the intrinsic pathway of apoptosis. The present review discusses the different types of mitocans and their mechanism of action along with preclinical and clinical studies in AML.

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Section: Thiol Redox Inhibitorsmentioning

confidence: 99%

Targeting the mitochondria in acute myeloid leukemia

Sánchez-Mendoza

Rego

2017

Appl Cancer Res

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“…Among others, PML-RARA causes a block in differentiation which can be nevertheless resolved with pharmaceutical doses of all-trans retinoic acid (ATRA). [15] The oncogenic fusion protein AML1-ETO is result of a translocation involving the genes AML1 on chromosome 8 and ETO on chromosome 21 present in the AML-M2 subtype. AML1-ETO enhances stem cell maintenance and inhibits myeloid differentiation (as reviewed by Nimer et al).…”

Section: Introductionmentioning

confidence: 99%

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

et al. 2016

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The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21 CIP1 . Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34 + progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34 + progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34 + cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4_RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21 CIP1 mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21 CIP1 expression during APL differentiation. Highlights RBM38 and DND1 expression is attenuated in primary AML patients  Normal and leukemic neutrophil differentiation induces RBM38 and DND1 expression  New function for the RNA binding proteins RBM38 and DND1 in APL differentiation Keywords: RBM38, DND1, acute myeloid leukemia, acute promyelocytic leukemia, neutrophil differentiation

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“…Initially proven effective in achieving remissions in relapsed APL, ATO plus ATRA was recently demonstrated to be not-inferior to ATRA plus chemotherapy in the front-line setting for low-and intermediate-risk patients. 10,11 For APL patients who relapse and subsequently attain a CR2, and for some APL patients who are deemed high-risk for relapse in CR1, autologous hematopoietic SCT (HSCT) continues to have an important therapeutic role. [12][13][14][15] Little is known about the impact of ATO on subsequent autologous HSCT, but two cases of delayed hematopoietic recovery in patients treated with ATO have been reported.…”

Section: Introductionmentioning

confidence: 99%

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis

Mannis

Logan

Leavitt

et al. 2014

Bone Marrow Transplant

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A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P o0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P o 0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P o 0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

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Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia

Abstract: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

Cited by 1,290 publications

References 38 publications

Targeting the mitochondria in acute myeloid leukemia

Targeting the mitochondria in acute myeloid leukemia

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis

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