Cédric S Tremblay

CancerCare Manitoba · CancerCare Manitoba Research Institute

Endocytosis entails selective packaging of cell surface cargos in cytoplasmic vesicles, thereby controlling key intrinsic cellular processes as well as the response of normal and malignant cells to their microenvironment. The purpose of this review is to outline the latest advances in the development of endocytosis-targeting therapeutic strategies...

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21688-1

The IκB kinase complex, consisting of IKK1, IKK2 and the regulatory subunit NEMO, is required for NF-κB signalling following the activation of several cell surface receptors, such as members of the Tumour Necrosis Factor Receptor superfamily and the Interleukin-1 Receptor. This is critical for haematopoietic cell proliferation, differentiation, sur...

Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a pr...

The coordinated differentiation of hematopoietic stem and progenitor cells (HSPCs) into the various mature blood cell types is responsible for sustaining blood and immune system homeostasis. The cell fate decisions underlying this important biological process are made at the level of single cells. Methods to trace the fate of single cells are there...

The hierarchical model posits that acute leukemias arise from leukemia stem cells (LSCs), which display stem cell-like properties like long-term self-renewal and differentiation to generate the heterogeneity observed in the tumor at diagnosis. Elimination of LSCs and their ancestral clones, pre-leukemic stem cells (pre-LSCs), is critical for long-t...

The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its c...

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ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and...

ZEB2, a E-box binding homeobox transcription factor, is able to induce epithelial-to-mesenchymal transition in the context of solid tumors. As such, its expression is correlated with cancer cell invasion, dissemination and metastasis, but also with the acquisition of cancer stem cell properties and therapy resistance. Using conditional knockout mic...

Background: Myeloproliferative neoplasms (MPN) are a diverse group of hematopoietic stem cell disorders. JAK2V617F gain-of-function is the most prevalent mutation, accounting for more than 60% of MPNs. PRMT5 was initially identified as a JAK-binding protein. Its enzymatic function catalyses the symmetric di-methylation of arginine on a variety of s...

Stem Cell Leukemia (Scl or Tal1) and Lymphoblastic Leukemia 1 (Lyl1) are highly related members of the basic helix-loop-helix (bHLH) family of transcription factors that are co- expressed in the erythroid lineage. Previous studies suggest that Scl is essential for primitive erythropoiesis. However, analysis of single-cell RNA-sequencing data of ear...

Pre-leukemic stem cells (pre-LSCs) give rise to leukemic stem cells through acquisition of additional gene mutations and are an important source of relapse following chemotherapy. We postulated that cell-cycle kinetics of pre-LSCs may be an important determinant of clonal evolution and therapeutic resistance. Using a doxycycline-inducible H2B-GFP t...

Objective: The Hairy Enhancer of Split 1 (HES1) is a transcriptional repressor that regulates cellular proliferation and differentiation during development. We previously found an interaction between HES1 and Fanconi anemia (FA) proteins. FA is a hematological and developmental disorder caused by mutations in more than 20 different genes. Eight FA...

Since the end of the 20th century, the development of novel approaches have emerged to manipulate experimental models of hematological disorders, so they would more accurately mirror what is observed in the clinic. Despite these technological advances, the characterization of crucial genes for benign or malignant hematological disorders remains cha...

In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytic hypochromia caused by a V235G missense mutation in Dynamin 2 (Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific and have been implicated in four forms of human diseases: centronuclear myopathy, C...

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1 ⁺ (Ph ⁺ ) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RN...

SCL (TAL1) and LYL1 are the predominant bHLH transcription factors expressed in erythropoiesis. Using a conditional allele of Scl, we have previously demonstrated redundancy of Scl in adult erythropoiesis. Similarly, adult erythropoiesis is maintained in Lyl1-deficient mice. To determine if these factors can compensate for each other, we deleted Sc...

Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the lifetime maintenance of the blood and bone marrow, achieved through their differentiation into the myriad cellular components and their ability to generate additional stem cells via self-renewal. Identification of intrinsic and extrinsic factors that regulate how...

Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the G...

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Us...

Stem cell leukaemia (Scl) and Lymphoblastic lymphoma derived sequence 1 (Lyl1) are the only hematopoiesis-specific basic Helix-loop-helix (bHLH) transcription factors. During development, Lyl1 is unable to compensate for Scl; with death of Scl-null embryos at e9.5 due complete absence of primitive hematopoiesis and defective vascular development. I...

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate tha...

The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by th...

Purpose of review: Recent genome sequencing studies have identified a broad spectrum of gene mutations in T-cell acute lymphoblastic leukemia (T-ALL). The purpose of this review is to outline the latest advances in our understanding of how these mutations contribute to the formation of T-ALL. Recent findings: Aberrant expression of transcription...

Significance Fanconi anemia (FA) is a devastating disease associated with a progressive bone marrow failure (BMF) and clonal proliferation of primitive hematopoietic cells that leads to leukemia. In an effort to understand the molecular basis of BMF and leukemogenesis in FA, we recently uncovered a unique function of proteins associated with FA in...

Early thymocyte progenitor T-cell acute lymphoblastic leukemia (ETP-ALL) is a poor prognosis malignancy that has a distinct genetic basis characterized by activating mutations of the IL-7 signaling pathway. Recurrent mutations spanning Dynamin 2 (Dnm2), a gene encoding a large GTPase required for clathrin-mediated endocytosis, have been identified...

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these fact...

Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and increased susceptibility to cancer. Of the fifteen FA proteins, Fanconi anemia group C (FANCC) is one of eight FA core complex components of the FA pathway. Unlike other FA core complex proteins, FANCC is mainly localized in the cytoplasm,...

207 Normal thymic progenitors are devoid of self-renewal capacity, which is a distinctive stem cell property. These thymic progenitors progress into the thymus through several stages of differentiation (DN1, DN2-4, DP) before giving rise to CD4+ or CD8+ immunocompetent cells that are released into the periphery. Therfore, thymic output requires con...

T cells develop from bone marrow-derived self-renewing hematopoietic stem cells (HSC). Upon entering the thymus, these cells undergo progressive commitment and differentiation driven by the thymic stroma and the pre-T cell receptor (pre-TCR). These processes are disrupted in T-cell acute lymphoblastic leukemia (T-ALL). More than 70% of recurring ch...

Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that t...

3649 Poster Board III-585 The Notch1 pathway and pre-TCR signalling are critical regulators of thymocyte development that have been implicated in T-cell acute lymphoblastic leukemia (T-ALL). Although the pre-TCR is required for Notch-dependent T-ALL, the role of pre-TCR alpha (pTa) as a Notch1 target remains controversial. Previous work in our labo...

Mutations in one of the 13 Fanconi anemia (FA) genes cause a progressive bone marrow failure disorder associated with developmental abnormalities and a predisposition to cancer. Although FA has been defined as a DNA repair disease based on the hypersensitivity of patient cells to DNA cross-linking agents, FA patients develop various developmental d...

Fanconi anemia (FA) proteins are thought to play a role in chromosome stability and repair of DNA cross-links; however, these functions may not fully explain the developmental abnormalities and bone marrow failure that are characteristic of FA individuals. Here we associate the FA proteins with the Notch1 developmental pathway through a direct prot...

The function of the Fanconi anemia group C protein (FANCC) is still unknown, though many studies point to a role in damage response signaling. Unlike other known FA proteins, FANCC is mainly localized to the cytoplasm and is thought to act as a messenger of cellular damage rather than an effector of repair. FANCC has been shown to interact with sev...