Search

Pain-sensing nerve cells can mobilize blood stem cells in mice, with a component of chilli peppers being one stimulus. The finding holds the promise of improving procedures for stem-cell transplantation. Stimulation of nociceptive neurons mobilizes haematopoietic stem cells., Author(s): Anastasia N. Tikhonova, Iannis Aifantis Author Affiliations: Pain-sensing neurons mobilize blood stem cells from bone marrow The cardinal feature of blood stem cells is their ability to regenerate the [...]

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders (1), and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified (2,3); however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL4. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors., In recent studies, we and other researchers have revealed that PRC2 has a key tumour-suppressor function, catalysing the methylation of H3K27 (refs 2, 4, 6). Since net H3K27me3 levels are [...]

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling (1). In this study we report the presence of loss-of-function mutations [...]

Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex (2). Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations (3). Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue., Notch is essential for the emergence of definitive haematopoiesis (4), controls HSC differentiation to the T-cell lineage (5,6) and is a major oncogene, as most patients with T-cell acute lymphoblastic [...]

T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents (1). T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse (2.3). For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment (3). Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance (4). Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications., Recent studies have shown that mutations of the developmental regulator Notch1 can be identified in most T-ALL patients (7). It is estimated that activation of the Notch1 signalling pathway occurs [...]

Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH 1) in T cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11). GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Kruppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL., GSIs, which block the presenilin-[gamma]-secretase complex, inhibit the production of amyloidogenic [beta]-amyloid peptides involved in the pathogenesis of Alzheimer's disease and the activation of NOTCH receptors (1,2). The recent identification [...]

On their entry into the thymus, developing lymphocyte progenitors depend on signaling from the pre-T cell receptor (pre-TCR), which orchestrates differentiation, cell proliferation, and survival. The exact mechanism of pre-TCR-mediated suppression of T cell death remains unclear and controversial. Here, we identify Bim and Bid, 2 members of the BH3-only group of the BCL2 family, as important regulators of pre-T cell death. Both factors are highly expressed in proapoptotic thymocytes and their expression is suppressed on signaling through the pre-TCR. Their expression is directly regulated by the transcription factors FoxO3a and p53. Bid expression and p53 activity are related to the ongoing rearrangement of the TCR loci and induced DNA damage responses. Bim expression and FoxO3a nuclear translocation are directly controlled by the pre-TCR by means of its downstream kinase Akt/PKB. Interestingly, deletion of either gene on a pre-[TCR.sup.-/-] background rescues survival, but fails to induce further progenitor differentiation uncoupling the 2 processes. BCL2 family | cell death | pre-TCR signaling | T cell development

T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-[kappa]B pathway transcriptionally and via the I[kappa]B kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-[kappa]B in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-[kappa]B pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-[kappa]B as one of the major mediators of Notch1-induced transformation and suggest that the NF-[kappa]B pathway is a potential target of future therapies of T-ALL., Author(s): Tomas Vilimas [1, 6, 7]; Joaquina Mascarenhas [2, 6]; Teresa Palomero [3]; Malay Mandal [1]; Silvia Buonamici [1, 4]; Fanyong Meng [1]; Benjamin Thompson [1, 4]; Christina Spaulding [5]; [...]

Homing of bone marrow (BM)-derived progenitors to the thymus is essential for T cell development. We have previously reported that two subpopulations of common lymphoid progenitors, CLP-1 and CLP-2, coexist in the BM and give rise to lymphocytes. We demonstrate that CLP-2 migrate to the thymus more efficiently than any other BM-derived progenitors. Short-term adoptive transfer experiments revealed that CLP-2 homing involves P-selectin/ P-selectin glycoprotein ligand 1 interactions, pertussis toxin-sensitive chemoattractant signaling by CC chemokine ligand 25 through CC chemokine receptor 9, and binding of the integrins [alpha]4[beta]1 and [alpha]L[beta]2 to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Preferential thymus-tropism of CLP-2 correlated with higher chemokine receptor 9 expression than on other BM progenitors. Thus, CLP access to the thymus is controlled by a tissue-specific and subset-selective multistep adhesion cascade. cell trafficking | chemokines | integrin | lymphopoiesis | selectin