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3920 MLL-USP2: An Underestimated New Entity of MLL-Rearranged Leukemia Identified By NGS Analysis

Program: Oral and Poster Abstracts
Session: 603. Oncogenes and Tumor Suppressors: Poster III
Hematology Disease Topics & Pathways:
Diseases, Leukemia, ALL, AML, Technology and Procedures, Lymphoid Malignancies, Clinically relevant, Myeloid Malignancies, NGS
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Claus Meyer1*, Bruno Lopes, PhD2,3*, Aurélie Caye-Eude, PharmD4*, Hélène Cavé, PharmD, PhD4*, Chloé Arfeuille, PhD4*, Rosemary Sutton, PhD5*, Nicola Venn, BSc6*, Patrizia Larghero, PhD3*, Seung Hwan Oh, MD3,7*, Grigory Tsaur, MD, PhD8*, Marketa Zaliova9, Jan Zuna9, Vesa Juvonen, PhD10*, Renate Panzer-Grümayer, MD11*, Grazia Fazio, PhD12*, Giovanni Cazzaniga, PhD13, Mariana Emerenciano, PhD2* and Rolf Marschalek, PhD3*

1DCAL, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/M, Germany
2Division of Clinical Research, Instituto Nacional de Cancer, Rio de Janeiro, Brazil
3DCAL, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt am Main, Germany
4Department of Genetics, University Hospital Robert Debré, Paris, France
5Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, Australia
6Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, Australia
7Department of Laboratory Medicine, Inje University College of Medicine, Busan, Korea, Republic of (South)
8Regional Children Hospital, Yekaterinburg, Russian Federation
9CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic
10Dept. of Clinical Chemistry and Tykslab, University of Turku and Turku University Hospital, Turku, Finland
11Children's Cancer Research Institute and Medical University of Vienna, Vienna, Austria, Vienna, Austria
12Centro Ricerca Tettamanti, University of Milano-Bicocca, San Gerardo Hospital/Fondazione MBBM, Monza, Italy
13Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca Ospedale San Gerardo, Monza, MB, Italy

Chromosomal rearrangements of the MLL gene are responsible for 5-10% of all acute leukemias, biphenotypic leukemias and myelodysplastic syndromes. The large number of known MLL fusions (>80) renders a precise diagnosis a demanding task. Even though all MLL rearrangements are associated with high-risk acute leukemia, the outcome (poor or very poor) is influenced by the partner gene. The applied diagnostic methods (LDI-PCR and multiplex PCR) allows the identification of MLL fusion genes at the nucleotide level, providing important information on the genetics of leukemia patients, and patient-specific biomarkers. These biomarkers are used for monitoring of minimal residual disease in acute leukemia patients during and after therapy. Thus, the identification of MLL gene fusions is necessary for rapid clinical decisions to determine the best therapy regimen.

We have developed a customized NGS panel for MLL diagnostics to utilize state of the art technology at DCAL. With this new tool, the whole MLL gene is analyzed in contrast to the LDI-PCR where only the main MLL breakpoint cluster region (BCR-1) is covered. The first results of the NGS analysis of 84 patients identified MLL breakpoints located outside the main BCR-1 of MLL. Furthermore, a novel MLL partner gene USP2 was identified in 16 patients. All MLL-USP2 positive patients had a breakpoint located outside BCR-1 and within a newly defined breakpoint cluster region BCR-2. The BCR-2 site was also used in 2 other patients with MLL-AFF1 and one patient with MLL-MLLT3.

These findings reveal USP2 as a new entity for MLL rearrangements affecting indifferently children aged 3 months to 10 years old (mean 30 months) with no gender bias (M/F=1.3). Interestingly, only 5/16 affected children were below 1 year of age at diagnosis and thus treated according to the Interfant trial. Clinical presentation as well as outcome associated with this new entity deserves further investigation to define whether those patients should be allocated, as other MLL-rearranged ones, in high-risk treatment groups. More MLL patients should also be analyzed to get a better idea of the frequency of breakpoints within BCR-2, especially the frequency of MLL-USP2 fusions. Indeed, standard FISH analysis and CGH array do not permit reliable detection of this fusion, explaining why they remained undetected so far. The biology of this novel MLL rearrangement also deserves further investigation, considering that USP2 is the only MLL partner fused exclusively to BCR-2.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH