Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.

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Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.

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1725 Children up to the age of 5 years with trisomy 21 (T21, Down Syndrome) are at a 400-fold excess risk of developing myeloid leukemia (ML-DS). ∼5% of newborns with T21 develop a transient leukemia (TL). The megakaryoblastic phenotype by morphology and immunophenotyping is similar in both leukemias. Mutations in hematopoietic transcription factor GATA1 gene leading to expression of N-terminal truncated protein (GATA1s) have been detected in almost all TL and ML-DS patients and is the diagnostic genetic hallmark of these diseases. Aims: Fast and accurate identification is required to:confirm the diagnosis of TL or ML-DSconfirm the diagnosis of a GATA1s positive leukemia in children with no or little stigmata of Down Syndrome (T21 mosaic)monitor minimal residual disease (MRD)determine the pattern of GATA1 mutation in TL and ML-DS. Patients: Here we report the largest cohort of children (n=229) with TL (n=129) and ML-DS (n=100). The blast percentage of blasts were significant different (TL 43±3% vs. ML-DS 29 ±2%, p<0.03). Methods: The GATA1 mutation screening have been performed in two laboratories, the central reference of the AML-BFM Study Group (Hannover, Germany; TL n=90, ML-DS n=63) and at the Weatherall Institute of Molecular Medicine (Oxford, UK; TL n=39, ML-DS n=37). The AML-BFM Lab conducted direct sequencing. If this failed, sequencing was repeated with sorted blasts. If the result remained negative, subcloning of the blasts was performed (21 out of 137 patients). The Oxford lab screened all samples by WAVE and direct sequencing. The lower limit of blasts which allowed for successful detection of a GATA1 mutation was 2%. Results: GATA1 mutations were identified in 125 out of 129 (96%) newborns with TL and in 97/100 (97%) children with ML-DS. In 99% of cases GATA1 mutations were detected in exon 2; only in 2 cases were exon 3 mutations identified. GATA1 mutation were identified in 13 children with Down mosaic and acute leukemia (TL n=8; ML-DS n=5). The detection of GATA1 prevents intensive chemotherapy in newborns with TL and allowed reduced intensity chemotherapy to be administered in infants with ML-DS. The mutations are diverse: deletions (37%), point mutations (24%), duplications (23%) and insertions (16%). With exception of substitutions, which were uniquely detected in TL (n=2; 1.6%), no differences between TL and ML-DS have been observed. Mutations were predicted to result in a stop codon(66%), affect splicing (16%), produce a frameshift that produced a subsequent stop codon (7%), or alter the start codon (3%). No differences in these predicted outcomes was present between TL and DS-ML. Summary: Rapid detection of GATA1 mutations is possible in almost all children with T1 and mosaic T21 who develop TL or ML-DS with these approaches, even in samples where the blast count is as low as 2%. Mutation detection and conformation of the correct diagnosis is critical to ensure appropriate therapy is administered and to allow patient specific MRD monitoring. Disclosures: No relevant conflicts of interest to declare.