Correspondence to: Robert E. Gallagher, M.D., Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA; phone, 001-718-920-4180; fax, 001-718-798-7474; e-mail,ude.uy.mocea@hgallagr.

Abstract

Relapse of acute promyelocytic leukemia (APL) following all-trans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARα but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the non-mutant pretreatment APL cell population by a PML-RARα mutant subclone. Two patients relapsed in proximity of ATRA treatment, however, in 4 patients there was a 6 to 48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested ≥3 months before relapse at ≥1 in 10⁽¹⁰^{) sensitivity. In one patient, a functionally-weak mutation was detected at 10}^{sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARα mutant subclones and suggest that APL subclones harboring PML-RARα mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/survival advantage.}

Keywords: Acute promyelocytic leukemia, All-trans retinoic acid, PML-RARα mutations, mutant subclone dynamics, drug selection pressure

Abstract

Footnotes

Supported by grants CA56771 and CA21115 from the National Institutes of Health

Footnotes

References

1. Warrell RP., Jr Retinoid resistance in acute promyelocytic leukemia: New mechanisms, strategies and implications. Blood. 1993;82:1949–1953.[PubMed]
2. Gallagher RERetinoic acid resistance in acute promyelocytic leukemia. Leukemia. 2002;16:1940–1958.[PubMed][Google Scholar]
3. Chen Z-X, Xue Y-Q, Zhang R, Tao R-F, Xia X-M, Li C, Wang W, Zu W-Y, Yao X-Z, Ling B-JA clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413–1419.[PubMed][Google Scholar]
4. Delva L, Cornic M, Balitrand N, Guidez F, Miclea J-M, Delmer A, Teillet F, Fenaux P, Castaigne S, Degos L, Chomienne CResistance to all-trans-retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: Study of in vitro sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood. 1993;82:2175–2181.[PubMed][Google Scholar]
5. Ding W, Li YP, Nobile LM, Grills G, Carrera I, Paietta E, Tallman MS, Wiernik PH, Gallagher RELeukemic cellular retinoic acid resistance and missense mutations in the PML-RARα fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans etinoic acid and intensive chemotherapy. Blood. 1998;92:1172–1183.[PubMed][Google Scholar]
6. Zhou D-C, Kim S, Ding W, Schulz C, Warrell RP, Jr, Gallagher REFrequent mutations in the ligand binding domain of PML-RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood. 2002;99:1356–1363.[PubMed][Google Scholar]
7. Imaizumi M, Suzuki H, Yoshinari M, Sato A, Saito T, Sugawara A, Tsuchiya S, Hatae Y, Fujimoto T, Kakizuka A, Konno T, Iinuma KMutations in the E-domain of RARα portion of the PML/RARα chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia. Blood. 1998;92:374–382.[PubMed][Google Scholar]
8. Takayama N, Kizaki M, Hida T, Kinjo K, Ikeda YNovel mutation in the PML/RARalpha chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to retinoic acid in acute promyelocytic leukemia. Exp Hematol. 1998;29:864–872.[PubMed][Google Scholar]
9. Marasca R, Zucchini P, Galimberti S, Leonardi G, Vaccari P, Donelli A, Luppi M, Petrini M, Torelli GMissense mutations in the PML/RARα ligand binding domain in ATRA-resistant AS₂O₃ sensitive relapse acute promyelocytic leukemia. Haematologica. 1999;84:963–968.[PubMed][Google Scholar]
10. Cote S, Zhou D, Bianchini A, Nervi C, Gallagher RE, Miller WH., Jr Altered ligand binding and transcriptional regulation by mutations in the PML/RARα ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia. Blood. 2000;96:3200–3208.[PubMed]
11. Cassinat B, Chevret S, Zassadowski F, Balitrand N, Guillemot I, Menot M-L, Degos L, Fenaux P, Chomienne CIn vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome. Blood. 2001;98:2862–2864.[PubMed][Google Scholar]
12. Morosetti R, Grignani F, Liberatore C, Pelicci PG, Schiller GJ, Kizaki M, Bartram CR, Miller CW, Koeffler HPInfrequent alterations of the RARα gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes, and cell lines. Blood. 1996;87:4399–4403.[PubMed][Google Scholar]
13. Shao W, Benedetti L, Lamph WW, Nervi C, Miller WH., Jr A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RARα mutation. Blood. 1997;89:4282–4289.[PubMed]
14. Kitamura K, Kiyoi H, Yoshida H, Saito H, Ohno R, Naoe TMutant AF-2 domain of PML-RARα in retinoic acid-resistant NB4 cells: differentiation induced by RA is triggered directly through PML-RARα and its down-reguation in acute promyelocytic leukemia. Leukemia. 1997;11:1950–1956.[PubMed][Google Scholar]
15. Nason-Burchenal K, Allopenna J, Bégue A, Stéhelin D, Dmitrovsky E, Martin PTargeting of PML/RARα is lethal to retinoic acid-resistant promyelocytic leukemia cells. Blood. 1998;92:1758–1767.[PubMed][Google Scholar]
16. Cote S, Rosenauer A, Bianchini A, Seiter K, Vandewiele J, Nervi C, Miller WH., Jr Response to histone deacetylase inhibition of novel PML/RARalpha mutant detected in retinoic acid-resistant APL cells. Blood. 2002;100:261–270.[PubMed]
17. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JE, Ogden A, Shepherd L, Willman CL, Bloomfield CD, Rowe JM, Wiernik PHAll-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021–1028.[PubMed][Google Scholar]
18. Gallagher RE, Yeap BY, Bi W, Livak KJ, Beaubier N, Rao S, Bloomfield CD, Appelbaum FR, Tallman MS, Slack JL, Willman CLQuantitative real-time RT-PCR analysis of PML-RARα mRNA in adult acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood. 2003;101:2521–2528.[PubMed][Google Scholar]
19. Slack JL, Bi WB, Livak KJ, Beaubier N, Yu M, Clark M, Kim SH, Gallagher RE, Willman CLPre-clinical validation of a novel, highly sensitive assay to detect PML-RARα mRNA using real-time reverse-transcription-PCR. J Mol Diagnostics. 2001;3:141–149.[Google Scholar]
20. Gallagher RE, Willman CL, Slack JL, Andersen JW, Li YP, Viswanatha D, Bloomfield CD, Appelbaum FR, Schiffer CA, Tallman MS, Wiernik PHAssociation of PML-RARα fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: An intergroup molecular study. Blood. 1997;90:1656–1663.[PubMed][Google Scholar]
21. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CLMultiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–125.[PubMed][Google Scholar]
22. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai J-L, Philippe N, Facon T, Fenaux P, Preudhomme CSeveral types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood. 2002;100:1014–1018.[PubMed][Google Scholar]
23. Branson S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C, Joske D, Lynch K, Hughes TDetection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with poor prognosis. Blood. 2003;102:276–283.[PubMed][Google Scholar]
24. Grimwade D, Howe K, Langabeer S, Burnett A, Goldstone A, Solomon EMinimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RARα and RARα-PML assessment in patients who ultimately relapse. Leukemia. 1996;10:61–66.[PubMed][Google Scholar]
25. Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell RP, Jr, Miller WH., Jr Prognostic significance of minimal residual disease detection and PML/RAR-α isoform type: long-term follow-up in acute promyelocytic leukemia. Blood. 2001;98:2651–2656.[PubMed]
26. Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niedersieser D, Stoffregen EP, McWeeney S, Kovacs I, Park B, Druker BJ, Deininger MWHigh-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106:2128–2137.[PubMed][Google Scholar]
27. Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PPA role for PML and the nuclear body in genomic stability. Oncogene. 1999;18:7941–7947.[PubMed][Google Scholar]
28. Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PPThe promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood. 2005;105:3686–3690.[Google Scholar]
29. Di Croce L, Raker VA, Corsaro M, Faxi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PGMethyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–1082.[PubMed][Google Scholar]
30. Sanz MA, Tallman MS, Lo-Coco FTricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood. 2005;105:3019–3025.[PubMed][Google Scholar]
31. Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E, Pogliani EM, Di Bona E, Micalizzi C, Kropp M, Venditti A, Tafuri A, Mandelli FGemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004;104:1995–1999.[PubMed][Google Scholar]
32. Fenaux P, Chomienne C, Degos LAll-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol. 2001;38:13–25.[PubMed][Google Scholar]
33. Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL, Nowak MADynamics of chronic myeloid leukaemia. Nature. 2005;435:1267–1270.[PubMed][Google Scholar]
34. Komarova NL, Wodarz DDrug resistance in cancer: Principles of emergence and prevention. Proc Natl Acad Sci USA. 2005;102:9714–9719.[Google Scholar]
35. Melnick APredicting the effect of transcription therapy in hematologic malignancies. Leukemia. 2005;19:1109–1117.[PubMed][Google Scholar]