Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer1,2. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males3. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is significantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...

Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.

Increasing evidence suggests that mesenchymal stem/stromal cells (MSCs) carrying specific mutations are at the origin of some sarcomas. We have reported that the deficiency of p53 alone or in combination with Rb (Rb(-/-) p53(-/-)) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53(-/-) and Rb(-/-)p53(-/-) MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53(-/-) and Rb(-/-)p53(-/-) ASCs. In addition, gene expression profiling revealed transcriptome similarities between p53- or Rb-p53-deficient BM-MSCs/ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem to determine the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate toward the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors, which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development.

Notch1 activation is essential for T-lineage specification of lymphomyeloid progenitors seeding the thymus. Progression along the T cell lineage further requires cooperative signaling provided by the interleukin 7 receptor (IL-7R), but the molecular mechanisms responsible for the dynamic and lineage-specific regulation of IL-7R during thymopoiesis are unknown. We show that active Notch1 binds to a conserved CSL-binding site in the human IL7R gene promoter and critically regulates IL7R transcription and IL-7R α chain (IL-7Rα) expression via the CSL–MAML complex. Defective Notch1 signaling selectively impaired IL-7Rα expression in T-lineage cells, but not B-lineage cells, and resulted in a compromised expansion of early human developing thymocytes, which was rescued upon ectopic IL-7Rα expression. The pathological implications of these findings are demonstrated by the regulation of IL-7Rα expression downstream of Notch1 in T cell leukemias. Thus, Notch1 controls early T cell development, in part by regulating the stage- and lineage-specific expression of IL-7Rα.

Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.

The authors regret that a typographical error appeared in Fig. 3 A regarding a putative RBP-Jk binding site located at −996 bp in the mouse Il7ra gene promoter. The correct sequence is as follows: actcctgggagtt. The corrected figure appears below.

T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL.