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Key words: AIDS; HIV-1; Nef; CD4+ T cell; Cytotoxicity tion with nylon wool, and selective panning selection as described previously [16]. CD4+ T cells from lamina propria mononuclear cells (LPMCs) were a gift from Dr. M. Ito, Yamagata University School of Medicine. The T cells from PBMC and LPMC were cultured in Iscov's modified Dulbecco's medium (IMDM) containing 25 U/ml of rlL-2 and 10% heat-inactivated human AB serum (Gibco). Antibodies (Abs) and seraMouse monoclonal antibodies (mAbs), OKT-4 (anti-CD4) and OKT-8 (anti-CD8), were purchased from Ortho Diagnostic Inc.

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The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4CD8) or CD8 single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

MicroRNAs (miRNAs) are~21-25 nt long and interact with mRNAs to lead to either translational repression or RNA cleavage through RNA interference. A previous study showed that human immunodeficiency virus 1 (HIV-1) nef dsRNA from AIDS patients who are long-term non-progressors inhibited HIV-1 transcription. In the study reported here, nef-derived miRNAs in HIV-1-infected and nef transduced cells were identified, and showed that HIV-1 transcription was suppressed by nef-expressing miRNA, miR-N367, in human T cells. The miR-N367 could reduce HIV-1 LTR promoter activity through the negative responsive element of the U3 region in the 59-LTR. Therefore, nef miRNA produced in HIV-1-infected cells may downregulate HIV-1 transcription through both a post-transcriptional pathway and a transcriptional neo-pathway.