omparative molecular analysis of therapy-related and de novo acute romyelocytic leukemia

Therapy-related acute promyelocytic leukemia (t-APL) has been reported as a late complication of exposure to radiotherapy and/or chemotherapeutic agents targeting DNA topoisomerase II. We have analyzed in t-APL novel gene mutations recently associated with myeloid disorders. Unlike previous reports in acute myeloid leukemia (AML), our results showed neither IDHs nor TET2 mutations in t-APL. However we found an R882H mutation in the DNMT3A gene in a patient with t-APL suggesting a possible role of eywords: herapy-related leukemia cute Promyelocytic Leukemia DHs mutation this alteration in the pathogenesis of t-APL. © 2011 Elsevier Ltd. All rights reserved. NMT3A mutation ET2 mutation An increasing number of therapy-related acute promyelocytic eukemia (t-APL) cases have been reported in the past few years. he t-APL may arise both as a consequence of chemotherapy for primary tumor (in particular after anthracyclines administered or breast cancer) or, alternatively, following treatment of nonalignant conditions (such as multiple sclerosis, MS) with other opoisomeraseII (topoII) inhibitors like mitoxantrone (MTZ) [1]. lthough several studies on t-APL have shown drug-induced DNA leavage at specific sites in the PML gene the precise mechanism nderlying the t(15;17) formation in t-APL remains controversial. n addition, no studies have investigated in details the potential ontribution of genetic lesions other than t(15;17) to the pathoenesis of t-APL. We and others have recently characterized at the genomic level he t(15;17) in a series of t-APL developed after treatment of MS ith topoII inhibitors showing distinct distribution of breakpoint ∗ Corresponding author at: Department of Biopathology, University Tor Vergata, ia Montpellier 1, 00133 Rome, Italy. Tel. : +39 06 20903220; fax: +39 06 20903221. E-mail address: francesco.lo. coco@uniroma2.it (F. Lo-Coco). 145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. oi:10.1016/j.leukres. 2011.10. 015 clustering in this subset as compared to de novo APL cases [1,2]. In particular, a “hotspot” DNA region has been identified within PML intron 6 which represents a preferential site of topoII-induced DNA breaks. This finding, supported by DNA cleavage assays [1], suggests that topoII-mediated cleavage by topoII inhibitors could be relevant to the etiology of APL after exposure to these agents. Recently, new cytogenetically silent mutations in several genes have been described in acute myeloid leukemia (AML). These include the TET oncogene family member 2 (TET2), the family of isocitrate dehydrogenase (IDHs) genes and the DNM3TA gene, which are affected by mutations in approximately 15%, 10% and 22% of AML, respectively [3,4]. To date, few studies have analyzed the incidence of TET2, IDHs and DNMT3A gene mutations in de novo APL while, to the best of our knowledge, no mutational analyses of these genes in t-APL have been reported [3,4]. We investigated the mutational status of FLT3, TET2, IDH1, IDH2 and DNMT3A genes in t-APL as compared to de novo APL cases. Seventeen patients with t-APL and 24 patients with de novo APL were included in the study. The de novo APL cases were consecutively diagnosed and treated at the Department of Biopathology, T. Ottone et al. / Leukemia Research 36 (2012) 474– 478 475 Table 1 Main clinical features of t-APL and de novo APL patients. Patient ID Sex Primary disease Therapy primary disease Disease Age at time of t-APL/de novo APL diagnosis UPN 1 F Non-Hodgkin Lymphoma R-CHOPa t-APL 52 UPN 2 F multiple sclerosis MTZb t-APL 36 UPN 3 M Lewis-Sumner syndrome Ig and azathioprine t-APL 56 UPN 4 F Multiple sclerosis MTZ t-APL 46 UPN 5 F Multiple sclerosis MTZ t-APL 53 UPN 6 F Corpus uteri carcinoma Radiation t-APL 65 UPN 7 F Multiple sclerosis MTZ t-APL 29 UPN 8 F Hodgkin Lymphoma ABVDc and radiation t-APL 19 UPN 9 M Multiple sclerosis MTZ t-APL 50 UPN 10 F Multiple sclerosis MTZ t-APL 45 UPN 11 F Multiple sclerosis MTZ t-APL 33 UPN 12 M Prostate cancer Radiation + HTd t-APL 77 UPN 13 F Multiple sclerosis MTZ t-APL 59 UPN 14 M Histiocytoma Radiation t-APL 63 UPN 15 M Breast cancer Radiation t-APL 58 UPN 16 M Prostate cancer Radiation t-APL 79 UPN 17 M Multiple sclerosis MTZ t-APL 46 UPN 18 M – – de novo APL 45 UPN 19 M – – de novo APL 70 UPN 20 M – – de novo APL 61 UPN 21 M – – de novo APL 46 UPN 22 M – – de novo APL 51 UPN 23 M – – de novo APL 52 UPN 24 F – – de novo APL 62 UPN 25 M – – de novo APL 47 UPN 26 M – – de novo APL 19 UPN 27 M – – de novo APL 63 UPN 28 F – – de novo APL 27 UPN 29 F – – de novo APL 35 UPN 30 M – – de novo APL 68 UPN 31 M – – de novo APL 54 UPN 32 M – – de novo APL 77 UPN 33 F – – de novo APL 59 UPN 34 M – – de novo APL 29 UPN 35 M – – de novo APL 62 UPN 36 M – – de novo APL 37 UPN 37 M – – de novo APL 52 UPN 38 M – – de novo APL 33 UPN 39 F – – de novo APL 44 UPN 40 F – – de novo APL 36 UPN 41 F – – de novo APL 9 a Rituximab-cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone.