Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML.

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation.

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1.

CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro.

Online support community for adolescents and young adults (AYAs) with cancer: user statistics, evaluation, and content analysis.

Purpose: Peer support is an important unmet need among adolescent and young adult (AYA) cancer patients. This study was conducted to describe the use and evaluation of a Dutch secure online support community for AYA diagnosed with cancer between 18 and 35 years.

Methods: User statistics were collected with Google analytics.

Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell-mediated TNFα signaling.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood.

Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors.

Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear.

miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.

To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo.

The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis.

ETS fusion genes in prostate cancer.

Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer.

Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion.

The hematopoietic system sustains regeneration throughout life by balancing self-renewal and differentiation. To stay poised for mature blood production, hematopoietic stem cells (HSCs) maintain low-level expression of lineage-associated genes, a process termed lineage priming. Here, we modulated expression levels of Inhibitor of DNA binding (ID) proteins to ask whether lineage priming affects self-renewal of human HSCs.

ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21.

There is increasing evidence that some cancers are hierarchically organized, sustained by a relatively rare population of cancer-initiating cells (C-ICs). Although the capacity to initiate tumors upon serial transplantation is a hallmark of all C-ICs, little is known about the genes that control this process. Here, we establish that ID1 and ID3 function together to govern colon cancer-initiating cell (CC-IC) self-renewal through cell-cycle restriction driven by the cell-cycle inhibitor p21.

A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal.

Highly regenerative tissues such as blood must possess effective DNA damage responses (DDR) that balance long-term regeneration with protection from leukemogenesis. Hematopoietic stem cells (HSCs) sustain life-long blood production, yet their response to DNA damage remains largely unexplored. We report that human HSCs exhibit delayed DNA double-strand break rejoining, persistent gammaH2AX foci, and enhanced p53- and ASPP1-dependent apoptosis after gamma-radiation compared to progenitors.

Overexpression of prostate-specific TMPRSS2(exon 0)-ERG fusion transcripts corresponds with favorable prognosis of prostate cancer.

Purpose: To gain insight in the mechanism and clinical relevance of TMPRSS2-ERG expression in prostate cancer, we determined the specific characteristics of fusion transcripts starting at TMPRSS2 exon 1 and at a more upstream and less characterized exon 0.

Experimental Design: We used quantitative PCR analysis to investigate expression of wild-type TMPRSS2(exon 0) and TMPRSS2(exon 1) and of ERG fusion transcripts. Expression was tested in normal tissue samples, in prostate cancer cell lines and xenografts, and in fresh-frozen clinical prostate cancer samples (primary tumors and recurrences).

Expression of the androgen-regulated fusion gene TMPRSS2-ERG does not predict response to endocrine treatment in hormone-naïve, node-positive prostate cancer.

Background: Fusion of the androgen-regulated gene transmembrane protease, serine 2, TMPRSS2, to the v-ets erythroblastosis virus E26 oncogene homolog (avian), ERG, of the erythroblast transformation-specific (ETS) family is the most common genetic alteration in prostate cancer (PCa).

Objective: To determine whether expression of androgen-regulated TMPRSS2-ERG predicts response to endocrine treatment in hormone-naïve, node-positive PCa.

Design, Setting, And Participants: Eighty-five patients with histologically confirmed, node-positive PCa who were without treatment at the moment of lymph node dissection were analysed.

Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer.

In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14), and an endogenous retroviral repeat sequence (HERVK17).

Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer.

Recently, fusion of ERG to the androgen-regulated, prostate-specific TMPRSS2 gene has been identified as the most frequent genetic alteration in prostate cancer. At low frequency, TMPRSS2-ETV1 and TMPRSS2-ETV4 fusion genes have been described. In this study, we report two novel ETV4 fusion genes in prostate cancer: KLK2-ETV4 and CANT1-ETV4.

TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer.

Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer. We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer. All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon 1 or 2 sequences to ERG exon 4.

Androgen receptor modifications in prostate cancer cells upon long-termandrogen ablation and antiandrogen treatment.

To study the mechanisms whereby androgen-dependent tumors relapse in patients undergoing androgen blockade, we developed a novel progression model for prostate cancer. The PC346C cell line, established from a transurethral resection of a primary tumor, expresses wild-type (wt) androgen receptor (AR) and secretes prostate-specific antigen (PSA). Optimal proliferation of PC346C requires androgens and is inhibited by the antiandrogen hydroxyflutamide.

Not your "typical island woman": anorexia nervosa is reported only in subcultures in Curaçao.

Anorexia nervosa (AN), once thought to be a problem of wealthier, Western countries has now been documented in survey studies and case reports across geographic and economic groups; however, few epidemiological studies including interview have been done on these populations. We report on a comprehensive study on Curaçao, a Caribbean island in economic transition, where the majority of the population is of predominantly black African origin. As part of an epidemiological study on the island of Curaçao indigenous cases of AN were identified.

The incidence of anorexia nervosa on Curaçao.

Objective: Although anorexia nervosa was once thought to occur only in affluent societies, cases have now been documented across the globe. To examine whether anorexia nervosa emerges in societies undergoing socioeconomic transition, the authors studied the incidence of anorexia nervosa on the Caribbean island of Curaçao.

Method: The authors contacted the full range of community health and service providers on Curaçao, including dietitians, school counselors, and all 82 general practitioners.

Loss of a small region around the PTEN locus is a major chromosome 10 alteration in prostate cancer xenografts and cell lines.

We examined 11 prostate cancer xenografts and 4 cell lines for chromosome 10 alterations. Conventional comparative genomic hybridization (CGH) and array-based CGH revealed a pattern of loss of distal 10p, gain of proximal 10p and 10q, and loss of distal 10q. In addition, array CGH identified 2 high-level amplifications in the cell line PC3, homozygous deletions of PTEN in PC3 and in the xenografts PCEW, PC133, and PC324, and small single- or double-copy deletions around PTEN in PCEW, PC82, PC324, PC346, and LNCaP.

Deletion of chromosomal region 6q14-16 in prostate cancer.

A detailed analysis of chromosome 6 in DNAs from prostate cancers was performed, to define a region for subsequent search for cancer genes. DNA from 4 prostate cancer cell lines and 11 xenografts was used for CGH and whole-chromosome allelotyping with polymorphic microsatellite markers. Loss of proximal 6q was studied in more detail by high-density allelotyping of xenografts, cell lines and 19 prostate tumour specimens from TURP.