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Key Points• A novel RARa fusion gene, TBLR1-RARa, was found in rare cases of APL with t(3;17) chromosomal translocation.• TBLR1-RARa exhibited diminished transcriptional activity by recruiting more corepressors compared with RARa.The majority of acute promyelocytic leukemia (APL) cases are characterized by the PMLRARa fusion gene. Although the PML-RARa fusion gene can be detected in >98% of APL cases, RARa is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation.In this study, we identified a novel RARa fusion gene, TBLR1-RARa (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARa is the 10th RARa chimeric gene that has been reported up to now. TBLR1-RARa contained the B-F domains of RARa and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor a. As a result, TBLR1-RARa exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARa. In the presence of pharmacologic doses of ATRA, TBLR1-RARa could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARa could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARa target genes, and cell differentiation induction in a dose-and time-dependent manner. (Blood. 2014;124(6):936-945) IntroductionAcute promyelocytic leukemia (APL) is a special disease entity of acute myeloid leukemia. With the clinical use of all-trans retinoic acid (ATRA), APL turns into the most curable form of acute myeloid leukemia. The majority of APL cases are characterized by the fusion between the promyelocytic leukemia (PML) gene and the retinoic acid receptor a (RARa) gene, which is the consequence of t(15;17)(q22;q21) chromosomal translocation.1 Although the PML-RARa fusion gene can be detected in .98% of APL patients, 2 RARa is also found to be fused with other partner genes, 3-10 such as PML zinc finger (PLZF), nucleophosmin (NPM), and so forth. The RARa portion within fusion proteins is conserved, containing B-F domains of RARa, which cover the DNA-binding and ligand-binding motifs, so that RARa can be combined with retinoid X receptor a (RXRa) to bind the retinoic acid responsive element (RARE). 1,11 As a result, the fusion proteins usually form heterodimers with RXRa.9,12 A critical property that all RARa fusion proteins have in common is the ability to self-associate, forming homodimers. 13 The chimeric proteins, such as PML-RARa, PLZF-RARa, and NPMRARa, can robustly recruit transcriptional corepressors, including nuclear receptor corepressor/silencing mediator of retinoid and thyroid receptors (N-CoR/SMRT) and histone deacetylases (HDACs), to RARE and consequently result in ectopic repression of RARa target genes. 1,13,14 Transducin b-like 1 X-linked receptor 1 (TBLR1) ...

Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0566-8) contains supplementary material, which is available to authorized users.