Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

Barna et al. show that Myc-driven tumorigenesis is dependent on its ability to increase protein synthesis, as haploinsufficiency in ribosomal proteins decreases Myc-induced tumour formation. However, tumours caused by the loss of p53 were not affected. Myc stimulates cap-dependent protein translation at the expense of IRES-dependent translation, leading to the synthesis of a different set of proteins, and this effect is reversed by ribosomal protein haploinsufficiency. Of the proteins misregulated, Cdk11 is shown to be important for the effects of Myc on genomic instability that probably contributes to Myc-induced tumour formation. This study shows that Myc-driven tumourigenesis is dependent on its ability to increase protein synthesis, as haploinsufficiency in ribosomal proteins decreases Myc-induced tumour formation. However, tumours caused by the loss of p53, were not affected. Myc stimulates cap-dependent protein translation at the expense of IRES-dependent translation, leading to the synthesis of a different set of proteins, and this effect is reversed by ribosomal protein haploinsufficiency. The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA1,2. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE)3,4,5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ-Myc/+ mice. When accurate translational control is re-established in Eμ-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.

The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)–dependent translation in Dkc1 ^m mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1 ^m ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.

Mutations in DKC1 cause dyskeratosis congenita (DC), a disease characterized by premature aging and increased tumor susceptibility. The DKC1 protein binds to the box H + ACA small nucleolar RNAs and the RNA component of telomerase. Here we show that hypomorphic Dkc1 mutant ( Dkc1 ^m ) mice recapitulate in the first and second generations (G1 and G2) the clinical features of DC. Dkc1 ^m cells from G1 and G2 mice were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reductions of telomere length in Dkc1 ^m mice became evident only in later generations. These results suggest that deregulated ribosome function is important in the initiation of DC, whereas telomere shortening may modify and/or exacerbate DC.

All-trans retinoic acid binds to, inhibits and induces degradation of the active form of the prolyl isomerase Pin1, thereby turning off and on a variety of Pin1 substrate oncogenes and tumor suppressors, respectively. A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)—a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive—inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML–RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RARα gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes) in t(15;17) or t(11;17), respectively. APL in patients harboring t(15;17) responds well to retinoic acid (RA) treatment and chemotherapy, whereas t(11;17) APL responds poorly to both treatments, thus defining a distinct syndrome. Here, we show that RA, As ₂ O ₃ , and RA + As ₂ O ₃ prolonged survival in either leukemic PML-RARα transgenic mice or nude mice transplanted with PML-RARα leukemic cells. RA + As ₂ O ₃ prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RARα transgenic mice nor in nude mice transplanted with PLZF-RARα cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RA and RA + As ₂ O ₃ can induce, both in vivo and in vitro , the degradation of either PML-RARα or PLZF-RARα proteins, suggesting that the maintenance of the leukemic phenotype depends on the continuous presence of the former, but not the latter. Our findings lead to three major conclusions with relevant therapeutic implications: ( i ) the X-RARα oncoprotein directly determines response to treatment and plays a distinct role in the maintenance of the malignant phenotype; ( ii ) As ₂ O ₃ and/or As ₂ O ₃ + RA combination may be beneficial for the treatment of t(15;17) APL but not for t(11;17) APL; and ( iii ) therapeutic strategies aimed solely at degrading the X-RARα oncoprotein may not be effective in t(11;17) APL.