Isochromosome der(17)(q10)t(15;17) in acute promyelocytic leukemia resulting in an additional copy of the RARA-PML and loss of one p53 gene: report of two cases and literature review.

Izohromozom der(17)(q10)t(15;17) u akutnoj promijelocitnoj leukemiji rezultira dodatnom kopijom RARA-PML i gubitkom p53 gena: prikaz dva slučaja i pregled literature.

ACUTE promyelocytic leukemia; P53 antioncogene; REVERSE transcriptase polymerase chain reaction; TUMOR suppressor genes; DNA analysis; FLUORESCENCE in situ hybridization

Introduction. The isochromosome of the long arm of derivative chromosome 17, that originates from the translocation t(15;17) [ider(17)(q10)t(15;17), or ider(17q)] in acute promyelocytic leukemia (APL), is a rare chromosome aberration associated with a poor prognosis. Case report. We report the clinical and laboratory data associated with ider(17q) for two APL patients. Cytogenetic analysis of bone marrow cells in both cases showed a mosaic karyotype with the ider(17q); reverse transcription polymerase chain reaction (RT-PCR) was positive for the long (L) isoform of the retionic acid receptor alpha (PML-RARA) fusion transcript in each patient. Fluorescence in situ hybridization (FISH) analysis with the DNA probes for the PML gene on 15q24.1, and the RARA gene on 17q21.2, confirmed the extra copy of the RARA-PML fusion gene or ider(17q). Additionally, the FISH analysis with a DNA probe for the p53 gene on 17p13.1 confirmed loss of one copy of the universal tumor suppressor p53 in both patients. Conclusion. Both reported APL patients with ider(17q) had predominance of the clone with ider(17q) compared to those with t(15;17) and/or the normal karyotype, indicating that duplication of der(17) may provide a growth advantage allowing the relevant clone to become dominant. Moreover, as an important oncogenic event and poor prognostic factor in leukemia, loss of one gene copy of the tumor suppressor p53, may also contribute to this growth advantage. Although the clinical and prognostic significance for the patients with an ider(17q) remains unclear, cytogenetic and molecular-genetic analysis should be combined to reveal more details about this complex and rare chromosomal abnormality. [ABSTRACT FROM AUTHOR]

Uvod. Izohromozom dugog kraka derivata hromozoma 17, koji potiče od translokacije t(15;17) [ider(17)(q10)t(15;17) ili ider(17q)] u akutnoj promijelocitnoj leukemiji (APL), je retka hromozomska aberacija, povezana sa lošom prognozom. Prikaz bolesnika. Prikazali smo dva bolesnika čiji su klinički i laboratorijski podaci ukazivali na dijagnozu APL. Citogenetička analiza ćelija kostne srži oba bolesnika, pokazala je mozaičan kariotip sa ider(17q); reverzna transkripcija lančane reakcije polimeraze (RT-PCR) bila je pozitivna za dugu (L) izoformu fuzionog PML-RARA (retinoinska kiselina receptor alfa) transkripta. Analiza, fluorescentna in situ hibridizacija (FISH) sa DNA probama za PML gen na 15q24.1 i RARA gen na 17q21.2, potvrdila je prisustvo dodatne kopije RARA-PML fuzionog gena ili ider(17q). Pored toga, FISH analiza sa DNA probom za p53 gen na 17p13.1 potvrdila je gubitak jedne kopije univerzalnog tumor supresor gena p53 kod oba bolesnika. Zaključak. Kod oba bolesnika registrovana je dominacija patološkog klona sa ider(17q) u odnosu na klon sa klasičnom translokacijom t(15;17) i/ili klon sa normalnim kariotipom, što ukazuje na mogućnost da duplicirani der(17q) obezbeđuje proliferativnu prednost patološkom ćelijskom klonu. Nastankom ove aberacije dolazi i do gubitaka jedne kopije univerzalnog tumor supresor gena p53. To je dodatni, onkogeni događaj u neoplastičnom procesu i loš prognostički parameter za bolesnike sa APL, jer se time povećava efekat proliferativne prednosti leukemijskih ćelija. Iako klinički i prognostički značaj aberacije ider(17q) i dalje ostaje nejasan, kroz primer dva naša bolesnika možemo zaključiti da se isključivo kombinovanjem citogenetičkih i molekularno-genetičkih analiza mogu donekle obezbediti uslovi za razotkrivanje detalja o ovoj kompleksnoj i retkoj hromozomskoj abnormalnosti. [ABSTRACT FROM AUTHOR]

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