Skip to main content
  • Loading metrics

Retinoic Acid and Arsenic for Treating Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) was first identified as a distinct subtype of acute myeloid leukemia in 1957 by Leif Hillestad. It is called M3 in the French–American–British classification, with a variant type referred to as microgranular (M3v in the French–American–British nomenclature) [1]. APL is characterized by three features: (1) the presence of an accumulation of abnormal promyelocytes (see Glossary) that do not differentiate into mature granulocytes, (2) the occurrence of fibrinogenopenia and disseminated intravascular coagulation that is often worsened by chemotherapy, and (3) the presence of the specific chromosomal translocation t(15;17)(q22;q21) (Figure 1).


Apoptosis: A genetically determined process of cell death in which the cell uses specialized cellular machinery to kill itself and is then eliminated by phagocytosis or by shedding.

Caspase: A family of cysteine proteases with aspartate specificity that are essential intracellular death effectors.

Disseminated intravascular coagulation: A hemorrhagic disorder that occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels, resulting in depletion of clotting factors and tissue necrosis and bleeding.

Fibrinogenopenia: A decrease in concentration of fibrinogen in the blood.

Granulocyte: Terminally differentiated myelocyte or polymorphonuclear white blood cell (as a basophil, eosinophil, or neutrophil) with granule-containing cytoplasm.

Ligand-inducible transcription factors: Transcription factors that structurally have domains associated with DNA binding and ligand (hormone) recognition. When binding to its specific ligand, the transcription factor initiates a series of conformational changes and interacts efficiently with its specific DNA response element to recruit components of the transcriptional machinery.

Nuclear receptor superfamily: One of the most abundant classes of transcriptional regulators including receptors for steroid hormones (e.g., estrogens, glucocorticoids, and vitamin D3), RAs, thyroid hormones, and so on. These transcription factors regulate diverse functions such as homeostasis, reproduction, development, and metabolism in animals.

Promyelocyte: Granule-containing cell in bone marrow that is in an intermediate stage of development between myeloblasts and myelocytes and that gives rise to a granulocyte.

Proteasome: Proteolytic complex that degrades cytosolic and nuclear proteins.

Sumoylation: Post-translational modification of proteins by the small ubiquitin-like modifier SUMO.

Ubiquitin: A chiefly eukaryotic protein that when covalently bound to other cellular proteins marks them for proteolytic degradation.

Figure 1. The Three Features of APL

The three features of APL are (A) accumulation of abnormal promyelocytes, (B) fibrinogenopenia and disseminated intravascular coagulation, and (C) the chromosomal translocation t(15;17)(q22;q21), the resultant fusion transcripts, and variants.

APL accounts for 10%–15% of all cases of acute myeloid leukemia, with several thousand new cases diagnosed worldwide each year. Before the advent of differentiation therapy, APL was treated with anthracycline-based chemotherapy with a complete remission rate of 60%–76% and a 5-year event-free survival rate of 23%–35% [1,2].

Differentiation Therapy: From Hypothesis to Practice

Failure to differentiate terminally characterizes most, if not all, cancer cells of every origin. Whether the induction of differentiation could be a treatment strategy for cancers was hotly debated for decades before the advent of differentiation therapy.

An important discovery of the early 1970s was that myeloid leukemic cells could be reprogrammed to resume normal differentiation and to become non-dividing mature granulocytes or macrophages as a result of stimulation by various cytokines [3,4]. Based on this discovery, Leo Sachs at the Weizmann Institute of Science, Rehovot, Israel, hypothesized in 1978 that treatment with agents that induce cancer cells to complete differentiation could be a potential therapeutic option for patients with cancer [5]. In the early 1980s, Breitman and colleagues showed that retinoic acid (RA; Figure 2), a derivative of vitamin A, could induce terminal differentiation of human promyelocytic leukemic cells in vitro [6,7]. But the first clinical reports of using RA showed conflicting results. Some case reports showed beneficial effects of 13-cis RA in people with refractory or relapsed APL [8,9,10], but other reports showed that 13-cis RA was ineffective in treating APL [11].

Beginning in the early 1980s, the Shanghai Institute of Hematology conducted a series of experiments on differentiation therapy for APL. These experiments showed that all-trans RA (ATRA) could induce terminal differentiation of HL-60, a cell line with promyelocytic features, and fresh leukemic cells from patients with APL. These intriguing results were the impetus for a clinical trial. Twenty-four patients with APL were treated with ATRA (45 to 100 mg/m2/day). The result was dramatic: 23 patients (95.8%) went into complete remission (CR) without developing bone marrow hypoplasia or abnormalities of clotting. The remaining one patient achieved CR when chemotherapy was added [12]. Morphological maturation of bone marrow cells was found in all patients studied.

These results were later confirmed by many randomized studies in centers around the world. Further trials showed improved rates of CR, a decrease in severe adverse effects, and lengthening of the duration of remission. Table 1 summarizes the CR rates obtained in most large series of patients. Currently, ATRA combined with anthracycline-based chemotherapy can achieve CR in 90%–95% of patients with APL and overall 5-year disease-free survival in up to 75% of patients [13].

Table 1. CR Rate in Patients with APL Treated with ATRA (in Series Including More Than 50 Cases)

Arsenic: “Ancient Remedy Performs New Tricks”

Arsenic is a common, naturally occurring substance that exists in organic and inorganic forms in nature. The organic arsenicals consist of an arsenic atom in its trivalent or pentavalent state linked covalently to a carbon atom. There are three inorganic forms of arsenic: red arsenic (As4S4, also known as “realgar”), yellow arsenic (As2S3, also known as “orpiment”), and white arsenic, or arsenic trioxide (As2O3) [14].

Arsenic was used to treat chronic myelogenous leukemia in the 18th and 19th centuries, but was discarded as a treatment in the early 20th century because of its toxicity and the advent of radiation and cytotoxic chemotherapy. In the early 1970s, a group from Harbin Medical University in China found that intravenous infusions of Ailing-1, a crude solution composed of 1% arsenic trioxide with a trace amount of mercury chloride, induced CR in two-thirds of patients with APL. There was an impressive 30% survival rate after 10 years [15,16]. Pure arsenic trioxide at 0.16 mg/kg/day for 28–54 days was shown to induce CR in 14 out of 15 (93.3%) patients with relapsed APL [17]. Tetra-arsenic tetra-sulfide was also reported to be effective in APL treatment [18].

Since 1996, a large number of reports have shown that arsenic compounds induce a CR in 85% to 90% of patients with both newly diagnosed and relapsed APL [13]. Furthermore, after CR is achieved by arsenic compounds, a molecular remission (i.e., negative for promyelocytic leukemia RA receptor a [PML-RARa] transcript detected by reverse transcriptase polymerase chain reaction) is obtainable either with arsenic compounds or with ATRA and chemotherapy as consolidation treatment. It seems likely that arsenic compounds appropriately used in post-remission therapy could prevent recurrence and achieve a longer survival time [13,18].

Studies have shown that arsenic trioxide exerts dose-dependent dual effects on APL cells—it induces apoptosis (programmed cell death) preferentially at relatively high concentrations (0.5 × 10−6 to 2 × 10−6 M) and induces partial differentiation at low concentrations (0.1 × 10−6 to 0.5 × 10−6 M). The rapid modulation and degradation of the PML-RARa oncoprotein by arsenic trioxide could contribute to these two effects [19].

How Do ATRA and Arsenic Work at the Molecular Level?

To understand how ATRA and arsenic compounds act at the molecular level in treating APL, it is first important to understand the role of the PML-RARa fusion protein in the pathogenesis of APL.

Retinoids that are crucial for normal myeloid differentiation act via RA receptors (RARs) and retinoid X receptors (RXRs). These belong to the steroid/thyroid/retinoid nuclear receptor superfamily of ligand-inducible transcription factors. Both RAR and RXR families consist of three subtypes: α, β, and γ [20]. RARα forms a heterodimer with RXR and binds to RA response element to control the expression of target genes in the presence of physiological concentrations (10−9–10−8 M) of retinoids (Figure 3A).

Figure 3. Leukemogenic Effects of PML-RARá and Mechanisms of ATRA/Arsenic Trioxide in the Treatment of APL

(A) In the absence of RA, RARα/RXR heterodimers recruit the transcription corepressor (CoR), which mediates transcriptional silencing by mechanisms that include direct inhibition of the basal transcription machinery and recruitment of chromatin-modifying enzymes. Chromatin modification includes histone deacetylation, which leads to a compact chromatin structure that impairs the access of transcriptional activators. In the presence of physiological concentrations (10−9–10−8 M) of RA, the transcription corepressor is released and the coactivator is recruited to the RARα/RXR heterodimer, resulting in histone acetylation (AC) and overcoming of the transcription blockage.

(B) PML-RARα fusion protein binds to RARα target genes either on its own or with RXR and then recruits corepressors, leading to transcriptional repression and myeloid differentiation inhibition. PML-RARα oncoprotein sequesters the normal RXR and PML, inhibits the PML/P53 apoptotic pathway, and delocalizes PML and other proteins from the nuclear body. PML-RARα also may affect interferon (IFN) and other signal pathways. Abnormalities in protein tyrosine kinases (e.g., FLT3, c-fms) may collaborate with PML-RARα to cause APL.

(C) In the presence of pharmacological doses of ATRA or arsenic trioxide, the PML-RARα fusion is degraded in ways that are dependent on caspases and proteasomes. The degradation of PML-RARα may lead to derepression of transcription suppression and restoration of PML nuclear body structure. The blockade of other signaling pathways is also released, and the anti-apoptotic effect of PML-RARα is lost. ATRA also induces cyclic AMP (cAMP), which reverses the silencing of RXR, induces the expression of RA-induced genes and cyclooxygenase 1 (Cox 1), inhibits angiogenesis, and downregulates tissue factor. Subsequently, ATRA induces terminal cell differentiation, while arsenic trioxide induces partial differentiation and/or apoptosis of APL cells. The effects of ATRA and arsenic trioxide are indicated with red and blue arrows, respectively. AF2, the ligand-dependent transcriptional activation domain contained within the C-terminal E domain of RARα; D522, aspartate at residue 522; K160, lysine at residue 160; K490, lysine at residue 490; RARE, retinoic acid response element; SUG-1, a component of proteasome 19S complex that can bind with the activated AF2 domain of RARα.

More than 95% of patients with APL have the t(15;17)(q22;q21) translocation. This results in the fusion of the RARα gene on 17q21 and the promyelocytic leukemia (PML) gene on 15q22, which generates a PML-RARaα fusion transcript [21,22]. Variant translocations can also be detected in APL. The PML-RARα chimeric protein acts as a dominant negative mutant over wild-type RARα. The chimeric protein prevents activation of key target genes required for normal myeloid differentiation by sequestering RXR and other RARa cofactors and inhibiting normal RARα functions. The PML-RARα oncoprotein binds to RAR target genes either on its own or with RXR and then recruits histone deacetlyase complexes, which act as repressors of transcription.

PML-RARa may affect transcription in other pathways including those in which the transcription factor AP1 and interferon-responsive factors are involved. PML-RARα also binds to promyelocytic leukemia zinc finger (PLZF) protein and potentially affects its functions (e.g., growth suppression and transcription repression; control of developmental programs and differentiation) [20]. In addition, PML-RARα prevents apoptosis through delocalization of PML and other proteins from the nuclear body. Finally, PML-RARα may cooperate with activated mutations in protein tyrosine kinases, such as FLT3 [23], which confer proliferative and/or survival advantage to hematopoietic stem/progenitor cells. Whether PML-RARα affects the protein tyrosine kinase activity directly or indirectly is unclear. All these interactions of PML-RARα could be involved in the leukemogenesis of APL (Figure 3B).

ATRA and arsenic trioxide degrade and cleave the PML-RARα oncoprotein. Although we now have a good understanding of the molecular mechanisms underlying ATRA in differentiation therapy for APL, these mechanisms were shown long after the identification of the efficacy of this drug in treating the disease. Now it is well established that pharmacological concentrations of ATRA (10−7–10−6 M) exert their effects through targeting the PML-RARα oncoprotein, triggering both a change in configuration and degradation of the oncoprotein and the activation of transcription, leading to differentiation. Cleavage of the PML-RARα fusion protein by caspases at residue D522 has been shown in APL cells induced to differentiate by ATRA [24].

Further dissecting of the pathways involved in PML-RARα catabolism led to the discovery of ubiquitin/proteasome-mediated degradation of PML-RARα and RARα, which was dependent on the binding of SUG-1 in the AF2 transactivation domain of RARα with 19S proteasome [25,26]. In contrast to ATRA, which targets the RARα moiety of the fusion, arsenic targets the PML moiety of PML-RARα, through a still unclear mechanism, and causes PML to localize to the nuclear matrix and become sumoylated. Sumoylation at K160 is necessary for 11S proteasome recruitment and arsenic-trioxide-induced degradation, whereas sumoylation at K490 is needed for nuclear localization [27,28]. These results provide a striking similarity in the effect of these two otherwise unrelated agents (Figure 3C).

The final result of treatment with ATRA and arsenic trioxide is the degradation of the PML-RARa oncoprotein, which results in restoration of normal retinoid signaling. RXR and PML sequestration is abrogated, and PML nuclear body is restored. The corepressor is released and the coactivator is recruited and bound with RARα; thus, the transcription of target genes is derepressed. ATRA also induces cyclic AMP, a differentiation enhancer that boosts transcriptional activation, reverses the silencing of the transactivating function of RXR, and restores ATRA-triggered differentiation in mutant ATRA-resistant APL cells [29]. Additionally, ATRA induces the expression of RA-induced genes [30] and cyclooxygenase 1 [31], inhibits angiogenesis [32], downregulates the expression of tissue factor [33], and restores other signal pathways (e.g., the interferon pathway). Consequently, the abnormal promyelocytes differentiate and die through programmed cell death (Figure 3C).

Combining ATRA and Arsenic: A Cure for APL?

Since ATRA and arsenic trioxide degrade the PML-RARa oncoprotein via different pathways, and since studies in animal models have shown synergic effects of both drugs in prolonging survival or even eliminating the disease [34,35], the group at the Shanghai Institute of Hematology hypothesized that the combination of the two drugs might synergize in treating APL. To test this, 61 patients newly diagnosed with APL were randomized into three treatment groups: ATRA, arsenic trioxide, or a combination of the two drugs [36]. Although CR rates in all three groups were high (>90%), the time to achieve CR differed significantly—the time was shortest in patients treated with the combination. The disease burden (as reflected by fold change of PML-RARα transcripts at CR) decreased significantly more with combined therapy than with ATRA or arsenic trioxide monotherapy (p < 0.01), and this difference persisted after consolidation therapy (p < 0.05). Notably, all 20 patients in the combination group remained in CR whereas seven of 37 cases treated with monotherapy relapsed (p < 0.05) after a follow-up of 8–30 months (median, 18 months).

It seems that a combination of ATRA and arsenic trioxide for remission and maintenance treatment of APL produces better results than either of the two drugs used alone, in terms of the time required to achieve CR and the length of disease-free survival. We hope that the use of three treatments—ATRA, arsenic trioxide, and chemotherapy—will ultimately make APL a curable human acute myeloid leukemia [36].


The story of ATRA in the treatment of APL shows that by targeting the molecules critical to the pathogenesis of certain diseases, cells can be induced to return to normal. Differentiation therapy is therefore a practical method of treating human cancer that has shown consistent effectiveness in trials. The clarification of the underlying molecular abnormalities of APL is an example of the benefits of a close collaboration between bench and bedside, and is necessary for our understanding of the mechanisms of ATRA in differentiation therapy. It is clearly important to elucidate the molecular and cellular basis of a particular cancer if we are to further develop mechanism-based target therapies.

The sequencing of the human genome and ongoing functional genomic research are now accelerating the dissection of disease mechanisms and identification of therapeutic targets. This in turn may facilitate the screening of promising treatments. What we learn from developing curative treatment approaches to APL may help to conquer other types of leukemias and cancers.


This work was supported by the Chinese National Key Basic Research Project (973), the Chinese National High Tech Program (863), the National Natural Science Foundation of China, the Shanghai Municipal Commission for Science and Technology, the Shanghai Municipal Commission for Education, the Shanghai Municipal Commission for Health, the Shanghai Leading Academic Discipline Program, and the Samuel Waxman Cancer Research Foundation of the Shanghai Institute of Hematology. We appreciate long-term fruitful collaboration with Professors Hugues de Thé, Laurent Degos, Roland Berger, Michel Lanotte, and Christine Chomienne from Saint Louis Hospital, Paris; Professor Samuel Waxman from Mount Sinai Medical Center, New York; Dr. Arthur Zelent from Leukemia Research Fund Center, London; Professor Zhi-Xiang Shen from Rui-Jin Hospital, Shanghai; and Professor Ting-Dong Zhang from Harbin Medical University, Harbin, China.


  1. 1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, et al. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103: 620–625.
  2. 2. Chen Z, Wang ZY (2003) Acute promyelocytic leukemia. In: Pui CH, editor. Treatment of acute leukemias: New directions for clinical research. Towtowa (New Jersey): Humana Press. pp. 291–308.
  3. 3. Fibach E, Hayashi M, Sachs L (1973) Control of normal differentiation of myeloid leukemic cells to macrophages and granulocytes. Proc Natl Acad Sci U S A 70: 343–346.
  4. 4. Paran M, Sachs L, Barak Y, Resnitzky P (1970) In vitro induction of granulocyte differentiation in hematopoietic cells from leukemic and non-leukemic patients. Proc Natl Acad Sci U S A 67: 1542–1549.
  5. 5. Sachs L (1978) The differentiation of myeloid leukaemia cells: New possibilities for therapy. Br J Haematol 40: 509–517.
  6. 6. Breitman TR, Selonick SE, Collins SJ (1980) Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A 77: 2936–2940.
  7. 7. Breitman TR, Collins SJ, Keene BR (1981) Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 57: 1000–1004.
  8. 8. Flynn PJ, Miller WJ, Weisdorf DJ, Arthur DC, Brunning R, et al. (1983) Retinoic acid treatment of acute promyelocytic leukemia: In vitro and in vivo observations. Blood 62: 1211–1217.
  9. 9. Fontana JA, Rogers JS, Durham JP (1986) The role of 13 cis-retinoic acid in the remission induction of a patient with acute promyelocytic leukemia. Cancer 57: 209–217.
  10. 10. Nilsson B (1984) Probable in vivo induction of differentiation by retinoic acid of promyelocytes in acute promyelocytic leukaemia. Br J Haematol 57: 365–371.
  11. 11. Runde V, Aul C, Sudhoff T, Heyll A, Schneider W (1992) Retinoic acid in the treatment of acute promyelocytic leukemia: Inefficacy of the 13-cis isomer and induction of complete remission by the all-trans isomer complicated by thromboembolic events. Ann Hematol 64: 270–272.
  12. 12. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, et al. (1988) Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72: 567–572.
  13. 13. Wang ZY (2003) Ham-Wasserman lecture: Treatment of acute leukemia by inducing differentiation and apoptosis. Hematology (Am Soc Hematol Educ Program) 2003: 1–13.
  14. 14. Zhu J, Chen Z, Lallemand-Breitenbach V, de The H (2002) How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2: 705–713.
  15. 15. Zhang P, Wang SY, Hu LH (1995) Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 17: 58–62.
  16. 16. Sun HD, Ma L, Hu XC, Zhang TD (1992) Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin West Med 12: 170–171.
  17. 17. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, et al. (1997) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89: 3354–3360.
  18. 18. Lu DP, Qiu JY, Jiang B, Wang Q, Liu KY, et al. (2002) Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: A pilot report. Blood 99: 3136–3143.
  19. 19. Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, et al. (1997) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89: 3345–3353.
  20. 20. Melnick A, Licht JD (1999) Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.
  21. 21. de The H, Chomienne C, Lanotte M, Degos L, Dejean A (1990) The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347: 558–561.
  22. 22. Kakizuka A, Miller WH, Umesono K, Warrell RP, Frankel SR, et al. (1991) Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66: 663–674.
  23. 23. Shih LY, Kuo MC, Liang DC, Huang CF, Lin TL, et al. (2003) Internal tandem duplication and Asp835 mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in acute promyelocytic leukemia. Cancer 98: 1206–1216.
  24. 24. Nervi C, Ferrara FF, Fanelli M, Rippo MR, Tomassini B, et al. (1998) Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein. Blood 92: 2244–2251.
  25. 25. Zhu J, Gianni M, Kopf E, Honore N, Chelbi-Alix M, et al. (1999) Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha) and oncogenic RARalpha fusion proteins. Proc Natl Acad Sci U S A 96: 14807–14812.
  26. 26. vom Baur E, Zechel C, Heery D, Heine MJ, Garnier JM, et al. (1996) Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J 15: 110–124.
  27. 27. Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, et al. (2001) Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 193: 1361–1371.
  28. 28. Muller S, Matunis MJ, Dejean A (1998) Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 17: 61–70.
  29. 29. Kamashev D, Vitoux D, de The H (2004) PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med 199: 1163–1174.
  30. 30. Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, et al. (2000) Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 96: 1496–1504.
  31. 31. Rocca B, Morosetti R, Habib A, Maggiano N, Zassadowski F, et al. (2004) Cyclooxygenase-1, but not -2, is upregulated in NB4 leukemic cells and human primary promyelocytic blasts during differentiation. Leukemia 18: 1373–1379.
  32. 32. Kini AR, Peterson LA, Tallman MS, Lingen MW (2001) Angiogenesis in acute promyelocytic leukemia: Induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood 97: 3919–3924.
  33. 33. Zhu J, Guo WM, Yao YY, Zhao WL, Pan L, et al. (1999) Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents. Leukemia 13: 1062–1070.
  34. 34. Jing Y, Wang L, Xia L, Chen GQ, Chen Z, et al. (2001) Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 97: 264–269.
  35. 35. Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos L, et al. (1999) Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 189: 1043–1052.
  36. 36. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, et al. (2004) All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101: 5328–5335.
  37. 37. Bourgeois E, Chevret S, Sanz M, Dombret H, Thomas X, et al. (2003) Long term follow up of APL treated with ATRA and chemotherapy (CT) including incidence of late relapses and overall toxicity [abstract]. Blood 102(11). Abstract 483.
  38. 38. Iland H, Bradstock K, Chong L, Springall F, Ayling J, et al. (2003) Results of the APML3 Trial of ATRA, intensive idarubicin, and triple maintenance combined with molecular monitoring in acute promyelocytic leukemia (APL): A study by the Australasian leukemia and lymphoma Group (ALLG) [abstract]. Blood 102: Abstract 484.
  39. 39. Testi AM, Lo Coco F, Biondi A, Moleti ML, Giona F, et al. (2003) GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children [abstract]. Blood 102: Abstract 485.
  40. 40. Avvisati G, Petti MC, Lo Coco F, Testi AM, Fazi P, et al. (2003) AIDA: The Italian way of treating acute promyelocytic leukemia (APL), final act [abstract]. Blood 102: Abstract 487.
  41. 41. Ortega JJ, Martin G, Madero L, Deben G, Molines A, et al. (2003) Treatment with all-trans retinoic acid and anthracycline monochemotherapy in children with acute promyelocytic leukemia: A multicenter study by the PETHEMA group [abstract]. Blood 102: Abstract 2285.
  42. 42. Ades L, Chevret S, de Botton S, Thomas X, Dombret H, et al. (2003) Outcome of acute promyelocytic leukemia (APL) treated with all trans retinoic acid (ATRA) and chemotherapy (CT) in elderly patients (>60 years): The European group experience [abstract]. Blood 102: Abstract 2286.
  43. 43. Mandelli F, Latagliata R, Avvisati G, Fazi P, Rodeghiero F, et al. (2003) Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols. Leukemia 17: 1085–1090.