Rictor is essential in Notch-driven T-ALL pathogenesis.
LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in IntroductionT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy that occurs both in children and adults. Children have an overall survival rate of approximately 80% and adults approximately 30%-40%, with a significant proportion of patients succumbing to relapsed or resistant disease. 1 Chromosomal translocations in which TCR-regulatory elements drive abnormal expression of cellular protooncogenes are commonly the cause of T-ALL. 2 One such target is LMO2, 3,4 a LIM-only domain protein that mediates protein-protein interactions within a larger transcriptional regulatory complex containing GATA-1, TAL-1, and LDB1. 5 Approximately 9% of T-ALL cases exhibit abnormally increased LMO2 expression. 6 Lmo2-null mouse embryonic stem cells cannot contribute to mature hematopoietic lineages, 7 and Lmo2 Ϫ/Ϫ mice die at embryonic day 10.5 due to failure of erythropoiesis. 8 Normally, Lmo2 is expressed at the earliest stages of T-cell development, and its expression is down-regulated as T cells mature. 9 Transgenic mice that overexpress Lmo2 have a massive expansion of the immature thymocyte pool and develop T-ALL with a latency of between 10 and 12 months [10][11][12] Unlike normal thymocytes, those that overexpress Lmo2 have the potential to reconstitute thymi and differentiate into mature thymocytes, an ability that can be maintained for at least 4 serial transplantations. 13 Immature thymocytes overexpressing Lmo2 transcribe genes that are normally restricted to more primitive hematopoietic stem cells, suggesting that Lmo2 confers an increase in cellular self-renewal and a stem cell-like phenotype. 13 The long latency between the initiation of Lmo2 overexpression and the development of frank T-ALL implies that cooperating genetic events are required for tumorigenesis. In X-SCID human gene therapy trials, vector-induced activation of LMO2 accompanied the development of T-ALL in 4 patients whose leukemic blasts exhibited biallelic loss of the CDKN2A tumor suppressor locus or overexpression of BMI-1, a CDKN2A repressor; activating NOTCH1 mutations also occurred independently. 14-16 Therefore, CDKN2A deletion and NOTCH1 mutations each appear to accelerate tumorigenesis induced by LMO2 overexpression.CDKN2A (also designated INK4A-ARF) is deleted in more than 70% of T-ALL cases, 6,17 and encodes 2 intimately linked but functionally distinct tumor suppressors, p16 INK4A and p14 ARF (p19 Arf in the mouse), which counter cell proliferation in response to oncogenic stress. 18 The cyclin D-dependent kinase inhibitor p16 INK4A maintains the retinoblastoma protein in its hypophosphorylated growth-suppressive state to prevent entry into the DNAsynthetic (S) phase of the cell-division cycle. In contrast, p14 ARF inhibits the HDM2 E3 ubiquitin ligase (Mdm2 in the mouse) to induce p53, thereby triggering cell-cycle arrest or apoptosis. 18 The Cdkn2a (Ink4a-Arf) locus is epigenetically silen...
CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor. Constructs containing point mutations and truncations were expressed in Daudi human B lymphoblastoid cells to systematically determine the requirement for individual CD19 cytoplasmic tyrosines in these responses. Evidence for activity was found for Y330, Y360, and Y421 as well as that previously published for Y391. Precipitates formed with phosphopeptides consisting of CD19 sequences flanking these residues were used to screen for cytoplasmic proteins that mediate signaling. Phosphopeptide Y330 precipitated Grb2 and Sos, whereas phosphopeptides Y391 and Y421 both precipitated Vav and phospholipase C-γ2. These molecules also were found associated with native CD19. In mapping studies with altered constructs, CD19 Y330 and/or Y360 were necessary for binding Grb2 and Sos. Vav associated with CD19 constitutively in unstimulated cells by a tyrosine-independent mechanism requiring the portion of CD19 encoded by exons 9–12. After B cell Ag receptor stimulation, Vav association was tyrosine-dependent, but binding was influenced by multiple residues. However, when maximally phosphorylated by pervanadate, Y391 and, to a lesser extent, Y421 were sufficient. CD19 Y391 was also both necessary and sufficient for binding phospholipase C-γ2. Thus, different tyrosines along the CD19 cytoplasmic domain provide scaffolding for the formation of complexes of different signaling molecules.
IntroductionT-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 20% of all pediatric lymphoblastic leukemias and comprises a significant proportion of cancers affecting children and adolescents. 1 Advances in treatment, focusing largely on dose intensification in multiagent therapeutic regimens, have produced remarkable cure rates, with overall survival of approximately 80%. Nonetheless, T-ALL is overly represented among relapsed ALL cases, and the dose-intensive therapy required to improve its cure imposes its own disease burden.Activating mutations of NOTCH1 have been found in 50% of T-ALLs, making it one of the most commonly mutated genes in this disease. 2 Notch is a cell-surface receptor expressed in many developing organ systems, in which Notch ligands function in conjunction with other morphogens, including Wnt, Hedgehog, and bone morphogenic proteins, to program cell fate decisions. 3 The Notch receptor is formed by intracellular proteolytic cleavage of a single polypeptide chain, the 2 resulting subunits undergoing dimerization and transport to the plasma membrane. 4 When bound by its ligands (members of the delta/jagged family), the transmembrane receptor is cleaved extracellularly by an ADAM protease and intracellularly by ␥-secretase, thereby releasing the intracellular Notch (ICN) domain into the cytoplasm. After transport into the cell nucleus, the ICN complexes with DNA-binding partner proteins to activate target genes. Mutations in Notch may affect its heterodimerization domain, which reduces or eliminates ligand dependency of the receptor, or they may target the intracellular proline-, glutamic acid-, serine-, and threonine-rich domain, thereby stabilizing the active, intracellular signaling moiety. 2,4,5 These 2 classes of mutations can occur concomitantly in up-regulating Notch target gene expression.Notch transcriptional activity directs virtually every stage of T-cell development, from the earliest commitment of bone marrowderived progenitors to the T-lymphoid lineage through stages of thymocyte maturation to double-positive (DP) CD4 ϩ /CD8 ϩ cells. 5,6 Although malignant thymocytes that typify Notch1-associated T-ALL are usually arrested at the DP stage, DP progenitors do not appear to be the tumor-initiating population. Instead, tumorigenic cells arise from more immature T-cell progenitors that ultimately generate monoclonal tumors expressing unique T-cell receptor (TCR)- chains and diverse TCR-␣ chains. 7 Although leukemogenesis is independent of the pre-TCR, per se, ICN1 overexpression cannot induce leukemia in cells that lack pre-TCR signaling, implying that malignant transformation occurs after pre-TCR signaling but before completion of ␣ chain rearrangement. [7][8][9] Although the extent to which NOTCH1 mutations represent founding oncogenic events in T-ALLs has been debated, 10,11 robust mouse models of T-ALL driven by activated Notch1 implicate this pathway as an appealing target for therapeutic intervention. 4,5,[11][12][13] Occurring more frequently than mutati...
Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.
BackgroundEvidence-based guidelines for sickle cell disease (SCD) health maintenance and management have been developed for primary health care providers, but not for individuals with SCD. To improve the quality of care delivered to individuals with SCD and their caregivers, the main purposes of this study were to: (1) understand the desire for patient-centered guidelines among the SCD community; and (2) adapt guideline material to be patient-centered using community-engagement strategies involving health care providers, community -based organizations, and individuals with the disease.MethodsFrom May–December 2016, a volunteer sample of 107 individuals with SCD and their caregivers gave feedback at community forums (n = 64) and community listening sessions (n = 43) about technology use for health information and desire for SCD-related guidelines. A team of community research partners consisting of community stakeholders, individuals living with SCD, and providers and researchers (experts) in SCD at nine institutions adapted guidelines to be patient-centered based on the following criteria: (1) understandable, (2) actionable, and (3) useful.ResultsIn community forums (n = 64), almost all participants (91%) wanted direct access to the content of the guidelines. Participants wanted guidelines in more than one format including paper (73%) and mobile devices (79%). Guidelines were adapted to be patient-centered. After multiple iterations of feedback, 100% of participants said the guidelines were understandable, most (88%) said they were actionable, and everyone (100%) would use these adapted guidelines to discuss their medical care with their health care providers.ConclusionsIndividuals with SCD and their caregivers want access to guidelines through multiple channels, including technology. Guidelines written for health care providers can be adapted to be patient-centered using Community-engaged research involving providers and patients. These patient-centered guidelines provide a framework for patients to discuss their medical care with their health care providers.Electronic supplementary materialThe online version of this article (10.1186/s12878-018-0106-3) contains supplementary material, which is available to authorized users.
Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-B activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-B activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-B.
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