NOVEL Recurrent Genetic Aberrations in Pediatric AML: An AIEOP AML-2002 Study Group

Abstract 2494 Introduction. Acute myeloid leukemia (AML) is an heterogeneous disease with known specific recurrent genetic aberrations. The continuous and increasing identification of new genetic mutations has permitted to identify new subgroups with different prognosis. In the present work we evaluated the incidence of rare genetic abnormalities in pediatric AML such as del(4)(q12)FIP1L1-PDGFRA, t(16;21)(p11;q22)FUS-ERG, t(8;16)(p11;p13)MOZ-CBP, t(11;17)(q23;q12–21)MLL-AF17, t(4;11)(q35;q23)MLL-ArgB2, t(5;11)(q35;p15.5)NUP98-NSD1, t(3;5)(q25;q34)NPM1-MLF1, and MLLPTD. Methods. We selected 306 patients with AML other than acute promyelocytic leukemia, negative for known recurrent genetic abnormalities involving MLL, CBF-beta and FLT3 genes. RNA was extracted from fresh bone marrow at diagnosis, and multiplex RT-PCR was employed. Sequencing by Sanger method was applied to all positive cases to characterize breakpoints of fusion. The Kaplan-Meier method was used for estimating the probability of event-free survival (EFS). Results. We identified one patient each positive for t(16;21)(p11;q22)FUS-ERG, t(11;17)(q23;q12–21)MLL-AF17, and t(4;11)(q35;q23)MLL-ArgB2, respectively, this suggesting that these rearrangements are rare in pediatric AML. 2/306 patients had del(4)(q12)FIP1L1/PDGFRA, and 4/306 the t(8;16)(p11;p13)MOZ-CBP; both these anomalies should be investigated in larger cohorts for definining their prognostic value. Interestingly 6/306 (2%) patients had the t(3;5)(q25;q34)NPM1-MLF1, 6/306 (2%) the MLLPTD, and 8/306 (2.6%) were found to carry the t(5;11)(q35;p15.5)NUP98-NSD1. Since the t(5;11) fusion was recently associated to FLT3ITD, we enlarged the screening to 42 de novo AML harbouring FLT3ITD mutation enrolled in the AIEOP-LAM 2002 protocol finding that 6 of them (14%) had the NUP98-NSD1 fusion gene. We documented a poor EFS for patients with t(5;11)NUP98-NDS1 (n=12) as compared to patients negative for molecular lesions and enrolled in the LAM 2002-AIEOP protocol (25% vs 53.1% at 3 years, p Conclusions. We provide evidence that NUP98-NSD1 may be considered a recurrent translocation in pediatric AML with poor prognosis. Being cryptic to conventional karyotyping, we confirmed the need of using molecular approaches for a proper identification of this anomaly. We also suggest that the NUP98-NSD1 fusion gene be considered for a better evaluation of the FLT3ITD+ patients. Disclosures: No relevant conflicts of interest to declare.