The transcription factor Pax5 is essential for commitment of lymphoid progenitors to the B lymphocyte lineage. Pax5 fulfils a dual role by repressing B lineage 'inappropriate' genes and ...simultaneously activating B lineage-specific genes. This transcriptional reprogramming restricts the broad signaling capacity of uncommitted progenitors to the B cell pathway, regulates cell adhesion and migration, induces V(H)-DJ(H) recombination, facilitates (pre-)B cell receptor signaling and promotes development to the mature B cell stage. Conditional Pax5 inactivation in early and late B lymphocytes revealed an essential role for Pax5 in controlling the identity and function of B cells throughout B lymphopoiesis. PAX5 has also been implicated in human B cell malignancies, as it is deregulated by chromosomal translocations in a subset of acute lymphoblastic leukemias and non-Hodgkin lymphomas.
Lineage commitment and differentiation to a mature cell type are considered to be unidirectional and irreversible processes under physiological conditions. The commitment of haematopoietic ...progenitors to the B-cell lineage and their development to mature B lymphocytes critically depend on the transcription factor encoded by the paired box gene 5 (Pax5). Here we show that conditional Pax5 deletion in mice allowed mature B cells from peripheral lymphoid organs to dedifferentiate in vivo back to early uncommitted progenitors in the bone marrow, which rescued T lymphopoiesis in the thymus of T-cell-deficient mice. These B-cell-derived T lymphocytes carried not only immunoglobulin heavy- and light-chain gene rearrangements but also participated as functional T cells in immune reactions. Mice lacking Pax5 in mature B cells also developed aggressive lymphomas, which were identified by their gene expression profile as progenitor cell tumours. Hence, the complete loss of Pax5 in late B cells could initiate lymphoma development and uncovered an extraordinary plasticity of mature peripheral B cells despite their advanced differentiation stage.
STAT5 and interleukin 7 (IL-7) signaling are thought to control B lymphopoiesis by regulating the expression of key transcription factors and by activating variable (V(H)) gene segments at the ...immunoglobulin heavy-chain (Igh) locus. Using conditional mutagenesis to delete the gene encoding the transcription factor STAT5, we demonstrate that the development of pro-B cells was restored by transgenic expression of the prosurvival protein Bcl-2, which compensated for loss of the antiapoptotic protein Mcl-1. Expression of the genes encoding the B cell-specification factor EBF1 and the B cell-commitment protein Pax5 as well as V(H) gene recombination were normal in STAT5- or IL-7 receptor alpha-chain (IL-7Ralpha)-deficient pro-B cells rescued by Bcl-2. STAT5-expressing pro-B cells contained little or no active chromatin at most V(H) genes. In contrast, rearrangements of the immunoglobulin-kappa light-chain locus (Igk) were more abundant in STAT5- or IL-7Ralpha-deficient pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and the developmental ordering of immunoglobulin gene rearrangements by suppressing premature Igk recombination in pro-B cells.
The transcription factor E2A controls the initiation of B lymphopoiesis, which is arrested at the pre-pro-B cell stage in E2A-deficient mice. Here, we demonstrate by conditional mutagenesis that E2A ...is essential for the development of pro-B, pre-B, and immature B cells in the bone marrow. E2A is, however, dispensable for the generation of mature B cells and plasma cells in peripheral lymphoid organs. In contrast, germinal center B cell development is impaired in the absence of E2A despite normal AID expression and class-switch recombination. Molecular analysis revealed that E2A is required not only for initiating but also for maintaining the expression of
Ebf1,
Pax5, and the B cell gene program in pro-B cells. Notably, precocious
Pax5 transcription from the
Ikzf1 locus promotes pro-B cell development in E2A-deficient mice, demonstrating that ectopic
Pax5 expression is sufficient to activate the B lymphoid transcription program in vivo in the absence of E2A.
Epigenetic Priming in Cancer Initiation Vicente-Dueñas, Carolina; Hauer, Julia; Cobaleda, César ...
Trends in cancer,
06/2018, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Recent evidence from hematopoietic and epithelial tumors revealed that the contribution of oncogenes to cancer development is mediated mainly through epigenetic priming of cancer-initiating cells, ...suggesting that genetic lesions that initiate the cancer process might be dispensable for the posterior tumor progression and maintenance. Epigenetic priming may remain latent until it is later triggered by endogenous or environmental stimuli. This Opinion article addresses the impact of epigenetic priming in cancer development and in the design of new therapeutic approaches.
Cellular plasticity is the capacity that cells have to change their fate and adopt a new identity. Plasticity is essential for normal development and for tissue regeneration and, in an experimental ...setting, for the induction of pluripotency. All these processes involve a reprogramming of the cellular identity, mediated by signals from the environment and/or by internal changes at the transcriptional and epigenetic levels. Tumorigenesis is a process in which normal cells acquire a new malignant identity and give rise to a clonal aberrant population. This is only possible if the initiating cell has the necessary plasticity to undergo such changes, and if the oncogenic event(s) initiating cancer has the essential reprogramming capacity so as to be able to lead a change in cellular identity. The molecular mechanisms underlying tumoral reprogramming are the pathological counterparts of the normal processes regulating developmental plasticity or experimentally-induced reprogramming. In this review we will first revise the main features of non-pathological examples of reprogramming, and then we will describe the parallelisms with tumoral reprogramming, and we will also delineate how the precise knowledge of the reprogramming mechanisms offers the potential for the development of new therapeutical interventions. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
•Plasticity is the capacity of cells for changing their identity and becoming different cell types.•Reprogramming to pluripotency allows in vitro conversion of almost any cell into a pluripotent progenitor.•Tumorigenesis is the process of reprogramming a normal cell into a pathological one with stem cell properties.•There are many functional and conceptual parallelisms between reprogramming to pluripotency and tumoral reprogramming.•Understanding the role of plasticity and reprogramming in tumorigenesis will open new avenues for research and therapy.
PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. ...Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL-6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.
Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being ...actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the dimethylation of Histone 3 in Lysine 36 (H3K36me2). Until recently, it was considered as merely an intermediate towards the generation of the trimethylated form, but recent data support a more specific role in many aspects of genome regulation. H3K36 dimethylation is mainly carried out by proteins of the Nuclear SET Domain (NSD) family, among which NSD2 is one of the most relevant members with a key role in normal hematopoietic development. Consequently, NSD2 is frequently altered in several types of tumors—especially in hematological malignancies. Herein, we discuss the role of NSD2 in these pathological processes, and we review the most recent findings in the development of new compounds aimed against the oncogenic forms of this novel anticancer candidate.
Childhood B-Cell Preleukemia Mouse Modeling Isidro-Hernández, Marta; Alemán-Arteaga, Silvia; Casado-García, Ana ...
International journal of molecular sciences,
07/2022, Letnik:
23, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a ...“multi-step” or “multi-hit” mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these “first-hits” occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic “hits” will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the “multi-step” process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.
B-cell acute lymphoblastic leukaemia (B-ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of ...normal stages of B-cell differentiation. B-ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B-ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, the cells responsible for maintaining the disease appear to differ between the different types of B-ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B-ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B-cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B-cells and propose research avenues for addressing these issues in the future.
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