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.