Acute promyelocytic leukemia (APL) is characterized by the promyelocytic leukemia-retinoic acid receptor a (PML-RARA) fusion. In rare instances, RARA is fused to other partners, which dictate sensitivity to targeted therapies. Chen et al previously reported in Blood a novel TBLR1-RARA fusion, which is all-trans-retinoic acid (ATRA)-insensitive in vivo, in a t(3;17)(q26;q21)-harboring APL. 1,2 Here, we report another new RARA fusion resulting from the same translocation in a variant APL patient.The patient was a 36-year-old man who presented with fatigue, dyspnea, and easy bruising for 2 weeks. Complete blood count revealed a hemoglobin level of 5.4 g/dL, platelet count of 41 3 10 9 /L, and white blood cell count of 3.6 3 10 9 /L with 60% hypergranular blasts. Clotting profile showed a decreased fibrinogen level and prolonged prothrombin time but normal activated partial thromboplastin time. Bone marrow (BM) examination showed 68% of blasts with morphology similar to those in peripheral smear ( Figure 1A). The blasts were positive for myeloperoxidase, CD13, CD15, CD33, and CD117 but negative for CD34 and HLA-DR by flow cytometry. A diagnosis of APL was suggested and ATRA (45 mg/m 2 per day) was initiated while awaiting molecular findings. On day 4 of ATRA therapy, the patient developed differentiation syndrome (DS) with fluid retention and pleural effusions. Steroids and diuretics were started, and the 7 1 3 induction chemotherapy was commenced with cytarabine (200 mg/m 2 ) and daunorubicin (60 mg/m 2 ). A morphological complete remission was confirmed at day 30. Figure 1B-C) but the expected TBLR1-RARA fusion previously identified in t(3;17) was absent. No mutations in FLT3, NPM1, CEBPA, DNMT3A, RUNX1, K/NRAS, WT1, or IDH1/2 were detected. Using 59-rapid amplification of complementary DNA ends, we found that RARA was fused to another 3q26 gene called fibronectin type III (FN3) domain containing 3B (FNDC3B) in our patient. Subsequent RT-PCR confirmed the fusion between exon 24 of FNDC3B and exon 3 of RARA ( Figure 1D), which is involved in all other RARA fusions. FNDC3B was originally identified as an adipocyte differentiation factor.3 It contains 9 FN3 domains, which are implicated in protein interactions. The full-length FNDC3B-RARA transcript is predicted to encode a 1461-amino acid protein, containing 8 FN3 domains of FNDC3B as well as the DNA-binding and ligand-binding domain of RARA ( Figure 1E). Two reciprocal RARA-FNDC3B transcripts were also detected. The major transcript involves an in-frame fusion between RARA exon 2 and FNDC3B exon 25, whereas the minor transcript involves an out-offrame fusion between the same RARA exon and FNDC3B exon 26 ( Figure 1D). These transcripts are expected to generate 205-and 111-amino acid proteins, respectively ( Figure 1E). Both FNDC3B-RARA and RARA-FNDC3B fusions were undetected after the patient

RUNX1 encodes a Runt-related transcription factor that is critical for hematopoiesis. In this study, through a combinatorial molecular approach, we characterized a novel t(5;21)(q13;q22) translocation involving RUNX1 that was acquired during the progression of myelodysplastic syndrome to acute myeloid leukemia (AML) in a pediatric patient. We found that this translocation did not generate RUNX1 fusion but aberrantly upregulated RUNX1. This upregulation was attributed to the disruption of long-range chromatin interactions between the RUNX1 P2 promoter and a silencer in the first intron of the gene. Characterization of the silencer revealed a role of SNAG repressors and their corepressor LSD1/KDM1A in mediating the effect. Our findings suggest that chromosomal rearrangements may activate RUNX1 by perturbing its transcriptional control to contribute to AML pathogenesis, in keeping with an emerging oncogenic role of RUNX1 in leukemia.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0881-2) contains supplementary material, which is available to authorized users.

H elicase-like transcription factor is a SWI/SNF chromatin remodeling factor involved in various biological processes. However, little is known about its role in hematopoiesis. In this study, we measured helicase-like transcription factor mRNA expression in the bone marrow of 204 adult patients with de novo acute myeloid leukemia. Patients were dichotomized into low and high expression groups at the median level for clinicopathological correlations. Helicaselike transcription factor levels were dramatically reduced in the low expression patient group compared to those in the normal controls (n=40) (P<0.0001). Low helicase-like transcription factor expression correlated positively with French-American-British M4/M5 subtypes (P<0.0001) and complex cytogenetic abnormalities (P=0.02 for ≥3 abnormalities; P=0.004 for ≥5 abnormalities) but negatively with CEBPA double mutations (P=0.012). Also, low expression correlated with poorer overall (P=0.005) and event-free (P=0.006) survival in the intermediate-risk cytogenetic subgroup. Consistent with the more aggressive disease associated with low expression, helicase-like transcription factor knockdown in leukemic cells promoted proliferation and chromosomal instability that was accompanied by downregulation of mitotic regulators and impaired DNA damage response. The significance of helicase-like transcription factor in genome maintenance was further indicated by its markedly elevated expression in normal human CD34 + hematopoietic stem cells. We further demonstrated that helicase-like transcription factor was a RUNX1 target and transcriptionally repressed by RUNX1-ETO and site-specific DNA methylation through a duplicated RUNX1 binding site in its promoter. Taken together, our findings provide new mechanistic insights on genomic instability linked to helicase-like transcription factor deregulation, and strongly suggest a tumor suppressor function of the SWI/SNF protein in acute myeloid leukemia.