Pre-B cell receptor signaling in acute lymphoblastic leukemia. B cell precursors in human bone marrow are destined to die unless they are rescued through survival signals from a successfully assembled pre-B cell receptor. For this reason, defects in components of the pre-B cell receptor signaling chain cause a severe block of early B cell development in humans. Likewise, B cell lineage acute lymphoblastic leukemia (ALL) cells are arrested at early stages of B cell development. In this proposal, we test the hypothesis that the developmental arrest in B cell lineage ALL predominantly reflects aberrant pre-B cell receptor function. B cell lineage ALL represents by far the most frequent malignancy in children and is also common in adults. Despite significant advances over the past four decades, cytotoxic treatment strategies have recently reached a plateau with cure rates at 80 percent for children and 55 percent for adults. Relapse after cytotoxic drug treatment, initial drug-resistance and dose-limiting toxicity are among the most frequent complications of current therapy approaches. For this reason, pathway-specific treatment strategies in addition to cytotoxic drug treatment seem promising to further improve therapy options for ALL patients. In preliminary studies for this proposal on 148 cases of pre-B cell-derived human ALL, we found that ALL cells carrying an E2A-PBX1- or MYC- gene rearrangement are -like normal pre-B cells- highly selected for the expression of a functional pre-B cell receptor. In striking contrast, ALL cells with other cytogenetic abnormalities (e.g. BCR-ABL1- or MLL-AF4) lack expression of a functional pre-B cell receptor in virtually all cases. In a proof-of-principle experiment, we studied pre-B cell receptor function during progressive leukemic transformation of pre-B cells in BCR-ABL1-transgenic mice: Interestingly, signaling from the pre-B cell receptor and the oncogenic BCR-ABL1 kinase are mutually exclusive and only """"""""crippled"""""""" pre-B cells that fail to express a functional pre-B cell receptor are permissive to transformation by BCR-ABL1. As opposed to ALL cells with BCR-ABL1- or MLL-AF4-fusion gene, pre-B cell receptor signaling is active in E2A-PBX1- or MYC-transformed ALL, because these cells exhibit a vigorous Ca2+ signal in response to pre-B cell receptor engagement. Based on these findings, we hypothesize that ALL can be subdivided into two groups based on whether pre-B cell receptor signaling enables (Type I) or suppresses (Type II) leukemic growth. Studying primary human ALL xenografts and transgenic mouse models for Type I and Type II ALL, we propose in Aim 1 to establish characteristic key differences of pre-B cell receptor signaling in the two subgroups.
In Aim 2, we propose to identify the requirements for pre-B cell receptor-dependent survival signaling in Type I ALL as potential targets for pharmacological inhibition. Conversely, we propose in Aim 3 to elucidate the mechanisms of pre-B cell receptor-inactivation in Type II ALL and how functional pre-B cell receptor signaling induces apoptosis in Type II ALL cells. Given that pre-B cell receptor signaling in this subgroup of ALL effectively suppresses leukemic growth, our goal in Aim 3 is to interfere with these inactivation mechanisms to restore pre-B cell receptor-dependent apoptosis-signaling in Type II ALL cells. The proposed discrimination between Type I and Type II ALL resembles the classification of mature B cell lymphoma, in which subgroups can be distinguished based on the presence (i.e. Non-Hodgkin's lymphoma) and absence (i.e. Hodgkin's lymphoma) of B cell receptor expression. The central goal of this proposal is to establish the role of pre-B cell receptor signaling during malignant transformation and clonal evolution of ALL and to target individual components of its signaling cascade for the development of novel pathway-specific therapy approaches for ALL.
Pre-B cell receptor signaling in acute lymphoblastic leukemia. B lymphocytes are not only the cells that produce antibodies as part of the human immune system, they are also the cell of origin in most cases of acute lymphoblastic leukemia (ALL). ALL represents by far the most frequent type of cancer in children and is also a common disease in adults. For many years, patients with ALL are treated with chemotherapy and current treatment protocols lead to cure rates of 80 percent for children and 55 percent for adult patients with ALL. Our goal is to better understand the biology of human ALL, namely as a catastrophic aberration of normal B lymphocyte development. During normal B lymphocyte development, the pre-B cell receptor represents a critical signaling unit that guides early B lymphocyte precursors on their path of maturation. If signaling from the pre-B cell receptor is compromised, as for instance in patients with innate immune defects, the B lymphocyte precursors are arrested in their development at a primitive stage -as in ALL cells. Therefore, we propose to investigate the function of the pre-B cell receptor signaling unit (1) as a potential target to disrupt aberrant cell signaling that promotes leukemic growth and (2) to restore normal pre-B cell receptor signaling in the leukemia cells.
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