Akutna promijelocitna leukemija bez t(15;17): molekularni dokazi atipične PML/RAR-α transkripcione varijante genskim sekvenciranjem

  • Vesna Djordjević Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Nataša Tošić University of Belgrade, Institute for Molecular Genetics and Genetic Engineering, Belgrade, Serbia
  • Marija Denčić-Fekete Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Marijana Virijević Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Jelica Jovanović Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Ljubomir Jaković Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Nada Kraguljac-Kurtović Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Andrija Bogdanović Clinical Center of Serbia, Clinic of Hematology, Belgrade, Serbia
  • Tatjana Kostić University of Belgrade, Institute for Molecular Genetics and Genetic Engineering, Belgrade, Serbia
  • Sonja Pavlović University of Belgrade, Institute for Molecular Genetics and Genetic Engineering, Belgrade, Serbia
DOI: https://doi.org/10.2298/VSP170620040D
Ključne reči: dijagnoza, hibridizacija in situ, fluorescentna, leukemija, promijelocitna, akutna, biologija, molekularna, polimeraza, reakcija stvaranja lanaca, reverzna transkripcija

Sažetak


Uvod. Precizno dijagnostikovanje akutne promijelocitne leukemije (APL), ne samo na osnovu morfoloških i kliničkih parametara, već i na molekularnom nivou, veoma je važno radi primene adekvatne ciljane terapije. Prikaz bolesnika. Prikazali smo bolesnicu, staru 62 godine, sa dijagnozom APL. Primenom standardne citogenetičke analize, kao i primenom fluorescentne in situ hibridizacije (FISH), nije bilo potvrđeno prisustvo t(15;17) kod opisane bolesnice. Primenom metode reverzna transkriptaza-lančana reakcija polimeraze (RT-PCR), identifikovana su dva atipična promyelotic leukemia/retinoic acid receptor alpha (PML/RAR-α) fuziona transkripta. Oba transkripta su predstavljala izoforme. Duži transkript je zadržao “okvir čitanja” i kodirao je funkcionalan PML/RAR-α aberantni protein, dok je kraći transkript bio van “okvira čitanja”. Zaključak. Naša studija ukazuje na potrebu za primenom molekularne metodologije u svakodnevnoj kliničkoj praksi. Precizna karakterizacija PML/RAR-α fuzionih transkipta čini osnovu za identifikovanje retkih bolesnika čije lečenje zahteva dodatni oprez. Prema našim saznanjima, ovo je tek peti slučaj opisanog atipičnog PML/RAR-α transkripta koji u sebi sadrži celokupan PML egzon 7a, a među njima jedini koji se nije mogao detektovati primenom citogenetičke i FISH analize. Svi ovde predstavljeni slučajevi su imali smrtni ishod. Zbog toga, naši rezulatati, zajedno sa sličnim slučajevima opisanim u literaturi, naglašavaju značaj detaljne identifikacije atipičnih PML/RAR-α fuzija, ne samo u svrhu prepoznavanja njihove uloge u procesu leukemogeneze, veći i u smislu procene njihovog uticaja na ishod lečenja.

Reference

Oku E, Imamura R, Nagata S, Takata Y, Seki R, Otsubo K, et al. Promyelocytic crisis of chronic myelogenous leukaemia during imatinib mesylate treatment. Acta Haematol 2006; 117(4): 191–6.

Pandolfi PP, Alcalay M, Fagioli M, Zangrilli D, Mencarelli A, Div-erio D, et al. Genomic variability and alternative splicing gen-erate multiple PML-RARα transcripts that encode aberrant PML proteins and PML-RARα isoforms in acute promyelocy-tic leukemia. EMBO J 1992; 11(4): 1397–407.

Saeed S, Logie C, Stunnenberg HG, Martens JH. Genome-wide functions of PML–RARα in acute promyelocytic leukaemia. Br J Cancer 2011; 104(4): 554–8.

Grimwade D, Howe K, Langabeer S, Davies L, Oliver F, Walker H, et al. Establishing the presence of the t(15; 17) in suspect-ed acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M. R. C. ATRA trial. M. R. C. Adult Leukaemia Working Party. Br J Haematol 1996; 94(3): 557–73.

Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Ci-oce M, et al. Fusion proteins of the retinoic acid receptor-α re-cruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391(6669): 815–8.

Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia. Hum Mol Genet 2001; 10(7): 769–75.

Zayed A, Couban S, Hayne O, Sparavalo N, Shawwa A, Sadek I, et al. Acute promyelocytic leukemia: a novel PML/RARα fusion that generates a frameshift in the RARα transcript and ATRA resistance. Leuk Lymphoma 2007; 48(3): 489–96.

Quignon F, De Bels F, Koken M, Feunteun J, Ameisen J, de Thé H. PML induces a novel caspase-independent death process. Nat Genet 1998; 20(3): 259–65.

Ibáñez M, Carbonell-Caballero J, García-Alonso L, Such E, Jimé-nez-Almazán J, Vidal E, et al. The mutational landscape of acute promyelocytic leukemia reveals an interacting network of co-occurrences and recurrent mutations. PLoS ONE 2016; 11(2): e0148346.

Lo-Coco F, Ammatuna E, Montesinos P, Sanz MA. Acute pro-myelocytic leukemia: recent advances in diagnosis and man-agement. Semin Oncol 2008; 35(4): 401–9.

Nasr R, Guillemin M, Ferhi O, Soilihi H, Peres L, Berthier C, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 2008; 14(12): 1333–42.

Gianni M, Fratelli M, Bolis M, Kurosaki M, Zanetti A, Paroni G, et al. RARα2 and PML-RAR similarities in the control of ba-sal and retinoic acid induced myeloid maturation of acute my-eloid leukemia cells. Oncotarget 2017; 8(23): 37041–60.

Barragán E, Bolufer P, Martı́n G, Cervera J, Moreno I, Capote FJ, et al. Identification of two atypical PML–RARα transcripts in two patients with acute promyelocytic leukemia. Leukemia Res 2002; 26(5): 439–42.

Chillon MC, González M, García-Sanz R, Balanzategui A, Gonzá-lez D, López-Pérez R, et al. Two new 3' PML breakpoints in t(15; 17)(q22; q21)-positive acute promyelocytic leukemia. Genes Chromosomes Cancer 2000; 27(1): 35–43.

Gonzalez M, Barragan E, Bolufer P, Chillon C, Colomer D, Bor-stein R, et al. Pretreatment characteristics and clinical outcome of acute promyelocytic leukaemia patients according to the PML-RARalpha isoforms: a study of the PETHEMA group. Br J Haematol 2001; 114(1): 99–103.

Slack JL, Willman CL, Andersen JW, Li YP, Viswanatha DS, Bloomfield CD, et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML-RAR alpha iso-form: results from intergroup protocol 0129. Blood 2000; 95(2): 398–403.

Vizmanos JL, Larrrayoz MJ, Odero MD, Lasa R, Gonzalez M, Novo FJ, et al. Two new molecular PML-RAR alpha variants: implications for the molecular diagnosis of APL. Haematolog-ica 2002; 87(8): ELT37.

van Dongen J, Macintyre E, Gabert J, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene tran-scripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIO-MED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13(12): 1901–28.

Kim MJ, Cho SY, Kim M, Lee JJ, Kang SY, Cho EH, et al. FISH-negative cryptic PML–RARA rearrangement detected by long-distance polymerase chain reaction and sequencing analyses: a case study and review of the literature. Cancer Genet Cytogenet 2010; 203(2): 278–83.

Lewis C, Patel V, Abhyankar S, Zhang D, Ketterling RP, McClure RF, et al.. Microgranular variant of acute promyelocytic leu-kemia with normal conventional cytogenetics, negative PML/RARA FISH and positive PML/RARA transcripts by RT-PCR. Cancer Genet 2011; 204(9): 522–3.

Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, et al. Characterization of acute promyelocytic leuke-mia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hé-matologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diag-nosis in Haematological Malignancies". Blood 2001; 96(5): 1297–308.

Brockman SR, Paternoster SF, Ketterling RP, Dewald GW. New highly sensitive fluorescence in situ hybridization method to detect PML/RARA fusion in acute promyelocytic leukemia. Cancer Genet Cytogenet 2003; 145(2): 144–51.

Han J, Kim K, Kim K, Park J, Kim J. Identification of PML–RARA rearrangement by RT-PCR and sequencing in an acute promyelocytic leukemia without t(15;17) on G-banding and FISH. Leuk Res 2007; 31(2): 239–43.

Soriani S, Cesana C, Farioli R, Scarpati B, Mancini V, Nosari A. PML/RAR-α fusion transcript and polyploidy in acute pro-myelocytic leukemia without t(15;17). Leuk Res 2010; 34(9): e261–3.

Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Laf-age-Pochitaloff M, et al. Genomic anatomy of the specific recip-rocal translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosomes Cancer 2003; 36(2): 175–88.

Ismail S, Ababneh N, Awidi A. Identification of Atypical PML-RARA Breakpoint in a Patient with Acute Promyelocytic Leukemia. Acta Haematol 2007; 118(3): 183–7.

Park TS, Kim JS, Song J, Lee K, Yoon S, Suh B, et al. Acute promyelocytic leukemia with insertion of PML exon 7a and partial deletion of exon 3 of RARA: a novel variant transcript related to aggressive course and not detected with real-time polymerase chain reaction analysis. Cancer Genet Cytogenet 2009; 188(2): 103–7.

De Angelis F, Breccia M. Molecular monitoring as a path to cure acute promyelocytic leukemia. Rare Cancers Ther 2015; 3(1–2): 119–32.

Gupta V, Yi Q, Brandwein J, Chun K, Lipton JH, Messner H, et al. Clinico-biological features and prognostic significance of pml/rarα isoforms in adult patients with acute promyelocytic leukemia treated with all trans retinoic acid (atra) and chemo-therapy. Leuk Lymphoma 2004; 45(3): 469–80.

Gallagher RE, Li YP, Rao S, Paietta E, Andersen J, Etkind P, et al. Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro respon-siveness to all-trans retinoic acid. Blood 1995; 86(4): 1540–7.

Objavljeno
2021/08/19
Broj časopisa
Vol. 77 Br. 1 (2020): Vojnosanitetski pregled
Rubrika
Prikaz bolesnika