All-Trans Retinoic Acid and Arsenic Trioxide Resistance of Acute Promyelocytic Leukemia with the Variant STAT5B-RARA Fusion Gene
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Letters to the Editor 1606 leukemia mouse model. This effect was proposed to be due, at REFERENCES least in part, to inhibition of FBXW7, a negative regulator of Notch 1 Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC et al. Gene 8 signaling. However, FBXW7 targets the degradation of other expression signatures define novel oncogenic pathways in T cell acute lympho- oncogenic proteins, such as c-Myc and mTOR, and the expression blastic leukemia. Cancer Cell 2002; 1: 75–87. of miR-223 is significantly elevated in TAL1-positive T-ALL cases 2 Cardoso BA, de Almeida SF, Laranjeira AB, Carmo-Fonseca M, Yunes JA, (Supplementary Figure 2), suggesting that the oncogenic function Coffer PJ et al. TAL1/SCL is downregulated upon histone deacetylase of this microRNA may extend beyond mere collaboration in Notch- inhibition in T-cell acute lymphoblastic leukemia cells. Leukemia 2011; 25: induced leukemia. 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Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene Leukemia (2013) 27, 1606–1610; doi:10.1038/leu.2012.371 to NPM1, NUMA1, PRKAR1A, FIP1L1, BCOR and STAT5B have been described.2–5 Prolonged disease-free survival of APL patients is achieved by combining all-trans retinoic acid (ATRA) and chemotherapy.6 The genetic hallmark of acute promyelocytic leukemia (APL) is In addition, treatment with arsenic trioxide (ATO) is of proven the t(15;17)(q22;q21)/PML-RARA rearrangement, which is detect- value in relapsed disease and also effective during induction able by fluorescence in situ hybridization (FISH) or reverse or consolidation therapy or both.5–7 However, the RARA transcription-polymerase chain reaction (RT-PCR) in 495% of fusion partner has an important impact on the biology of the morphologically defined APL.1,2 Moreover, seven variant fusion disease, in particular with regard to retinoic acid (RA) sensitivity. genes, which fuse RARA at low frequency to ZBTB16 or very rarely Therefore, APL can be divided in two disease subtypes: a RA- Accepted article preview online 28 December 2012; advance online publication, 22 January 2013 Leukemia (2013) 1567 – 1614 & 2013 Macmillan Publishers Limited Letters to the Editor 1607 RARA fusions.1–4 The sensitivity of variant RARA fusions to ATO has not been well documented, but ZBTB16–RARA-positive APL appears to be resistant.2,5 In this respect, it is noteworthy that the direct interaction of ATO with the PML moiety of the PML- RARA fusion protein leading to its degradation may provide an explanation for the specificity of ATO treatment in PML-RARA- positive APL.8 Herein, we describe a new case of APL with a STAT5B-RARA fusion in an adolescent—the first pediatric patient—which brings the number of patients with this rare APL variant to eight.9–15 Furthermore, we summarize the therapeutic approaches and clinical data of the cases described so far, demonstrating that patients with STAT5B-RARA-positive APL are unresponsive to both ATRA and ATO. This emphasizes the clinical importance of identifying this specific fusion gene in PML-RARA- negative APL. A 17-year-old boy underwent a routine checkup for a several day history of fatigue without any other clinical evidence of leukemia. However, 10% and 80% blast cells with AML M3 morphology and prominent Auer rods were detected in the peripheral blood and the bone marrow (BM), respectively. Immunophenotyping showed MPO þ , CD13 þ , CD33 þ , CD34 À , HLA-D À myeloid blast cells and, although clinically not apparent, coagulation was abnormal: fibrinogen 84 mg/dl, D-dimers 19.6 mg/ml. Cytogenetics revealed a 46,XY,?der(13), ?der(17q) karyotype without the typical t(15;17) and RT-PCR for PML-RARA was negative. Whereas FISH using the Vysis LSI PML/ RARA dual color dual fusion translocation probe resulted in an ambiguous FISH scoring with only 7% of interphase cells showing a split signal of the RARA probe (Figure 1a), hybridization with the Vysis LSI PML-RARA single fusion FISH probe kit suggested a deletion of RARA (Figure 1b). FISH employing the RARA-specific cosmid cos1241 and a STAT5B-specific BAC clone showed one co-localization of the probes (Figure 1c). Moreover, by applying additional FISH probes loss of genetic material at both loci as well as the presence of an inversion event were observed, indicating a complex intrachromosomal rearrangement. A more detailed description of the FISH data and all probes used are provided in the Supplementary Information. STAT5B-RARA-specific RT-PCR using primers STAT5Bex14-F1 50-GGCAATGGTTTGACGGTGTG-30 and RARAex3-R1 50-AGGGAGGGCTGGGCACTATC-30 and sequen- cing of the amplification product confirmed that, like in all cases described so far,9–15 STAT5B exon 15 was fused to RARA exon 3 Figure 1. FISH, RT-PCR and flow cytometric MRD analysis of STAT5B- (Figures 1d and e). RARA-positive APL. (a) Interphase FISH with the Vysis LSI PML/RARA dual color dual fusion translocation probe resulted in a splitting of Based on epidemiological data, 495% of APL harbor a PML-RARA rearrangement, and ZBTB16-RARA and NPM1-RARA the RARA probe (green signals) in only 7% of the cells, indicating a 1 possible RARA rearrangement. (b) Hybridization of a metaphase with account for o1% and 0.5% of the cases, respectively. Including the Vysis LSI PML/RARA single fusion FISH probe kit showing a the patient described herein, now eight STAT5B-RARA-positive APL complete deletion of the RARA probe (green signals).