Acute lymphoblastic leukemia

Summary

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated. In most cases, the cause is unknown. Genetic risk factors may include Down syndrome, Li–Fraumeni syndrome, or neurofibromatosis type 1. Environmental risk factors may include significant radiation exposure or prior chemotherapy. Evidence regarding electromagnetic fields or pesticides is unclear. Some hypothesize that an abnormal immune response to a common infection may be a trigger. The underlying mechanism involves multiple genetic mutations that results in rapid cell divisi

Official source

https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia

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The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Monique Coersmeyer

Project I: Chd7 Deficiency does not affect N1-driven T-ALL Induction and Maintenance nor impair Hematopoiesis Notch1 has been shown to be a key driver in pediatric T-cell acute lymphobastic leukemia (T-ALL). Previous work in the lab identified the chromatin-remodeling enzyme Chd7 to be highly over-expressed in aggressive versus pre-malignant disease. The aim of this project was to study if Chd7 is required during T-ALL initiation and disease maintenance as well as to characterize its role in the hematopoietic system under physiological and stress conditions. Therefore, Chd7 cKO animals were crossed with the MxCre deleter to ablate Chd7 specifically in BM progenitors. Chd7 deficiency did not induce any overt phenotype in the hematopoietic system, when studied under âsteadyâ state or stress conditions. In addition, Chd7 proved to be dispensable in the initiation and maintenance of murine and human Notch1-driven T-ALL. Therefore, we can rule out a role of Chd7 during late-stage leukemogenesis in Notch1-induced murine and human T-ALL. Project II: Serca2, a putative drug target to fight Notch1-driven T cell acute lymphoblastic leukemia, and its role in Hematopoiesis The Notch signalling pathway represents a bona fide drug target. We and Roti et al. performed a chemical compound screen and identified Cyclopiazonic acid (CPA) as potent Notch inhibitor. Biological target of this compound is the Sarco/Endoplasmic Reticulum ATPase2 (Serca2) that is involved in calcium homeostasis within the cell. Recently, it was shown that Serca2 regulates Notch1 (N1) receptor maturation and inhibition of Serca ATPases, using thapsigargin, blocks T-ALL progression in xenografts (Roti et al., 2013). The putative global effects of Serca2 inhibition on hematopoiesis have, however, not been addressed in this study. Aim of this study was to characterize the function of Serca2 in the hematopoietic system. Therefore, we crossed Serca2 cKO with MxCre to ablate Serca2 function in BM progenitors. Serca2 haploinsufficiency did not lead to any overt phenotype under physiological or competitive conditions. In contrast, Serca2ÎMxCre chimeras showed (i) impaired long-term reconstitution capacity upon transplantation, (ii) a severe reduction of total BM, splenic and thymic cellularity and (iii) an enrichment of KLS cells, the cell pool that contains HSCs. Mature lineages were highly apoptotic, while KLS were not majorly affected by apoptosis, resided predominantly in G0 phase of the cell cycle, exhibited slower cycling kinetics and were functionally impaired as they formed less and smaller colony forming units in vitro. Deregulated calcium levels can lead to an accumulation of unfolded proteins in the ER. In order to resolve ER stress, the cell activates the unfolded protein response (UPR). In case of unresolved ER stress, however, the cell undergoes apoptosis. We demonstrate that mature hematopoietic lineages up-regulate UPR-associated and pro-apoptotic genes, while KLS cells, in contrast, show unperturbed expression of these genes. In addition, we performed in vitro experiments, inhibiting Serca function in Lin- BM cells via thapsigargin (TH) treatment. TH induced severe apoptosis in the overall cell population, while KLS accumulated and were blocked in the G0 phase, closely mimicking Serca2 LOF in vivo. We therefore question the therapeutic approach of targeting Serca2 in N1-driven T-ALL due to severe side effects induced by Serca2 inactivation in the BM.

EPFL2015

Assessing the role of Hes1 and identification of target genes in human and murine T-ALL

Silvia Wirth

The Notch signalling pathway is an ancient cell signalling mechanism that enables short-range communications between cells and controls a broad spectrum of cell fates and developmental processes. In the haematopoietic system Notch signalling has been linked to physiological, but also to pathological phenotypes of T cell development. Identification of numerous activating mutations within the NOTCH1 receptor in human T cell acute lymphoblastic leukaemia (T-ALL) patient samples demonstrated that aberrant activation of this signalling pathway is a frequent event in T-ALL. Active Notch signalling leads to the expression of a plethora of genes that might be drivers or passengers in tumorigenesis including Hes1, which encodes a transcriptional repressor. We have therefore studied Hes1 in the context of T-ALL in mouse models that mimic human disease and in human T-ALL cell lines with the aim to evaluate whether Hes1 affects disease development and disease maintenance and to characterize its function on a molecular level. The first part of this study is dedicated to the functional characterisation of Hes1 in vivo in T-ALL mouse models and in vitro in human T-ALL cell lines. Using a retroviral bone marrow transplant model of T-ALL in which progenitor cells are transduced with a retrovirus expressing constitutive active Notch1 intracellular domain (NICD) we could show that Hes1 is not required in established, late stage T-ALL cells, but that it promotes tumour progression in the early stages of the disease. We have also investigated the function of HES1 in human T-ALL and can show that the overexpression of dominant negative versions of Hes1 in two patient derived cell lines (T-ALL1, CUTLL-1) does not affect proliferation or apoptosis, emphasising that HES1 does not affect cell viability once cells are fully transformed to the leukemic state. In the second part of the study we set out to systematically delineate the gene regulatory networks down-stream of Hes1 by combining RNA-seq and ChIP-seq analysis. Comparing the gene expression of murine premalignant, early stage NICD induced CD4+CD8+ DP cells in the presence and absence of Hes1 by RNA-seq, we unexpectedly found a predominant upregulation of genes in cells expressing Hes1 indicating that Hes1 might rather act as a positive regulator of transcription than as a transcriptional repressor of distinct target genes. Hes1 might influence transcription through secondary or indirect effects as combinatorial analysis of RNA-seq and ChIP-seq led to the identification of only a small number of potential direct target genes that are transcriptionally regulated by Hes1. In summary, the role of Hes1 in promoting the early stages of the disease appears to be highly complex and is likely to involve both direct and indirect control of gene regulatory networks.

EPFL2014

The evolutionarily conserved Notch signalling pathway controls a broad spectrum of cell fate decisions in organisms as diverse as fruit flies and mice. Whithin the murine haematopoietic system, Notch1 is indispensable for T cell development as conditional inactivation of Notch1 in bone marrow (BM) precursors results in a complete block in T-cell development and ectopic B-cell development in the thymus. Conversely, constitutive activation of Notch1 signalling plays a causative role in the development of acute T-cell lymphoblastic leukaemia (T-ALL). Numerous mutations within the Notch1 gene, which result in aberrent activation of Notch1 signalling, have been identified in > 50% of human T-ALL patients. Therefore, gain-of-function studies in murine models of T-ALL have been employed by many laboratories to elucidate the molecular mechanisms acting either cooperatively or downstream of oncogenic Notch1 signalling in development and progression of T-ALL. The best-characterized Notch1 target gene to date is a member of the bHLH family of transcriptional repressors, Hes1. This study focuses on the role of Hes1 as a mediator of Notch1 signalling in adult murine haematopoietic development, as well as the requirement for Hes1 in T-ALL development and maintenance. Conditional inactivation of Hes1 in adult murine BM cells results in severe thymic hypoplasia, while myeloid and B cell development remain unperturbed. Upon transplantation in congenic recipients, Hes1-/- progenitors give rise to only a small number of mature T cells. Hes1-inactivation does not however cause ectopic B-cell development in the thymus, and therefore does not phenocopy the loss of Notch1. Thus, while Notch1 signalling is indispensable for T versus B-cell fate specification, this function is not mediated exclusively via Hes1. Strikingly, in a competitive BM chimera setting, Hes1-/- progenitors completely fail to generate T cells. The mechanism by which Hes1 inactivation results in depleted T cell numbers remains to be elucidated, although we have shown that loss of Hes1 does not result in enhanced cell death. In addition, preliminary data are indicative of cell-cycle perturbation in Hes1-deficient immature T cells. Finally, we have demonstrated that upon IT transplantation, Hes1-deficient progenitors successfully give rise to T-cells at all stages of development. This data strongly indicates that Hes1 deficiency does not result in an intrinsic developmental defect but rather in the inability of T cell progenitors to efficiently home to the thymus from the BM. Upregulation of Hes1 expression has been observed in both human T-ALL cell lines as well as murine primary Notch1-induced T-ALL samples. However, the function of Hes1 as an effector of oncogenic Notch1 signalling in modulating disease onset or progression remained to be investigated. The requirement for Hes1 as a mediator of Notch1-induced T-ALL was addressed by inducing simultaneous deletion of Hes1 and expression of a dominant active form of Notch1 (NICD) in a murine model of T-ALL. Our data demonstrate that Hes1 is essential for the development of NICD-induced T-ALL. Loss of Hes1 prevents ectopic development of DP (CD4+CD8+) leukemic T cells in the BM and the subsequent accumulation of DP T cells in peripheral tissues, a hallmark of T-ALL, and consequently results in 10-fold increased life expectancy of experimental animals. We have further determined that Hes1 is required for the maintenance of T-ALL by inactivating Hes1 in a retrovirally pre-induced T-ALL model. Deletion of Hes1 in leukemic DP cells results in rapid cell death and enhanced survival. These data demonstrate that Hes1 is required as a mediator of Notch1 signalling in normal T cell development, and is indispensable to mediate the oncogenic effect of constitutive Notch1 activation in the induction of T-ALL.

EPFL2010