PB1710 ACUTE MYELOID LEUKEMIA WITH A RARE CRYPTIC T(8;16)(P11;P13) TRANSLOCATION AND MYST3/CREBBP FUSION
Authors: J. Brezinova, S. Ransdorfova, M. Valerianova, M. Onderkova, S. Izakova, Z. Zemanova, J. Markova, A. Vitek
Journal: HemaSphere (2019)

Background: The translocation t(8;16)(p11;p13) is a very rare cytogenetic finding in pediatric and adult de novo and therapy‐related acute myeloid leukemia (AML). It has been reported in 4‐7 per 1000 patients of AML. The vast majority of these cases have acute monocytic/myelomonocytic leukemia associated with hemophagocytosis by leukemic cells and with coagulopathy. The translocation fuses MYST3 gene on chromosome 8p11 with CREBBP gene on chromosome 16q13. Both MYST3 and CREBBP proteins have histone acetyltransferase activity and are involved in cell cycle control and transcriptional regulation. In adults this translocation represents a cytogenetically distinct group of patients with a poor prognosis. More cases have to be analyzed to elucidate the leukemic mechanisms and to recommend the standard therapy for patients with MYST3/CREBBP fusion. Aims: The aim of this study was to reveal new detail cytogenetic and clinical information about the rare cryptic t(8;16)(p11;p13) translocation with MYST3/CREBBP fusion in patient with AML and complex karyotype. Methods: A 53‐year‐old man was referred to our hospital in July 2018. According to cytologic and cytochemic findings diagnosis of monocytic AML (FAB M5b) was established. A classical cytogenetic analysis of bone marrow cells showed a complex karyotype, multicolor FISH (mFISH) confirmed the rearrangements of chromosomes 7, 8, and 16. Multicolor banding technique (mBAND) was used to detect multiple breakpoints on chromosomes 7 and 8. Based on the results of mBAND we deduced suspect MYST3/CREBBP gene fusion. The corresponding RNA levels were analyzed to confirm this hypothesis. Three pairs of primers were designed to detect all of the so far described fusion transcripts of MYST3 and CREBBP genes. RNA was isolated from mononuclear cells using TRIzol Reagent and cDNA was prepared using random hexamers and SuperScript II. The PCR product was treated by ExoSAP‐IT and directly sequenced on ABI Prism 310 genetic analyser using the Big Dye Terminator kit v. 3.1. Results: The peripheral blood count at diagnosis indicated a white blood cell count 32.5 x 10 9 /L, red blood cell count 4.21 x 10 12 /L, hemoglobin level of 124 g/L, and platelet count of 63.0 x 10 9 /L. Bone marrow aspiration revealed hypercellularity with increased number of pathological monocytic cells (78.4%) with 62.8% of blastic elements (monoblasts and promonocytes). Patient achieved complete remission one month after induction therapy. In December 2018 he has undergone the allogenic bone marrow transplantation. The karyotype at diagnosis was 46,XY,der(7)t(7;8)(p15.1;q22.1),der(8)t(8;16) (p11;p13)t(7;8)(p21;q11),der(16)t(8;16)(p11;p13) with multiple rearrangements of chromosomes 7 and 8 probably resulted of chromothripsis. Sequencing analysis revealed the previously described fusion of exon 17 of MYST3 to exon 2 of CREBBP genes, respectively. Specific primers and probe were designed to monitor minimal residual disease during treatment. After 4 months of treatment, a 2 log decrease of MYST3/CREBBP transcript was observed and normal karyotype 46,XY was found. Summary/Conclusion: Using combination of molecular cytogenetic and molecular genetic techniques we proved a cryptic t(8;16)(p11;p13) translocation not detectable by classical cytogenetic with MYST3/CREBBP fusion in a patient with monocytic AML. Because of the rarity of these cases, every new patient with this rearrangement adds the knowledge of clinic and biologic profile of this disease. Supported by MH CZ ‐DRO (IHBT, 00023736), RVO‐VFN64165, GACR P302/12/G157, Progres Q28/LF1.