The t(10;11)(p12;q23) chromosomal translocation in human acute myeloid leukemia results in the fusion of the MLL and AF10 genes. The latter codes for a novel leucine zipper protein, one of many MLL fusion partners of unknown function. In this report, we demonstrate that retroviral-mediated transduction of an MLL-AF10 complementary DNA into primary murine myeloid progenitors enhanced their clonogenic potential in serial replating assays and led to their efficient immortalization at a primitive stage of myeloid differentiation. Furthermore, MLL-AF10-transduced cells rapidly induced acute myeloid leukemia in syngeneic or severe combined immunodeficiency recipient mice. Structure/function analysis showed that a highly conserved 82-amino acid portion of AF10, comprising 2 adjacent ␣-helical domains, was sufficient for immortalizing activity when fused to MLL. Neither helical domain alone mediated immortalization, and deletion of the 29-amino acid leucine zipper within this region completely abrogated transforming activity. Similarly, the minimal oncogenic domain of AF10 exhibited transcriptional activation properties when fused to the MLL or GAL4 DNA-binding domains, while neither helical domain alone did. However, transcriptional activation per se was not sufficient because a second activation domain of AF10 was neither required nor competent for transformation. The requirement for ␣-helical transcriptional effector domains is similar to the oncogenic contributions of unrelated MLL partners ENL and ELL, suggesting a general mechanism of myeloid leukemogenesis by a subset of MLL fusion proteins, possibly through specific recruitment of the transcriptional machinery. IntroductionChromosomal translocations involving the MLL (HRX, ALL1, hTRX) gene at 11q23 produce a diverse array of fusion proteins that are associated with high-risk acute myeloid and lymphoid leukemias. 1 The MLL protein is required for normal hematopoiesis and has been implicated as an upstream regulator of Hox genes. [2][3][4] Increasing evidence supports a gain-of-function mechanism for leukemic transformation by MLL fusion proteins. 5,6 However, alternative mechanisms have been proposed. 7,8 Thus, defining the contributions of MLL fusion partners to the oncogenic activation of MLL is important for understanding the molecular pathogenetic roles for MLL chimeric proteins in a clinically aggressive subset of hematologic malignancies.More than 30 MLL fusion partners have been reported to date. 1 Most of these are novel proteins of unknown function that display structural heterogeneity. Thus, no common theme has emerged to account for their oncogenic roles in activating the leukemogenic properties of MLL. Some of the most frequent MLL partners, AF-4 (FEL), ENL, and ELL, display an ability to activate transcription under experimental conditions. 9-12 For ENL and ELL, domains with transcriptional effector properties coincide with regions that are necessary and sufficient, when fused to MLL, for transformation of murine myeloid progenitors by their respect...
Recognition of self is emerging as a theme for the immune recognition of human cancer. One question is whether the immune system can actively respond to normal tissue autoantigens expressed by cancer cells. A second but related question is whether immune recognition of tissue autoantigens can actually induce tumor rejection. To address these issues, a mouse model was developed to investigate immune responses to a melanocyte differentiation antigen, tyrosinase-related protein 1 (or gp75), which is the product of the brown locus. In mice, immunization with purified syngeneic gp75 or syngeneic cells expressing gp75 failed to elicit antibody or cytotoxic T-cell responses to gp75, even when different immune adjuvants and cytokines were included. However, immunization with altered sources of gp75 antigen, in the form of either syngeneic gp75 expressed in insect cells or human gp75, elicited autoantibodies to gp75. Immunized mice rejected metastatic melanomas and developed patchy depigmentation in their coats. These studies support a model of tolerance maintained to a melanocyte differentiation antigen where tolerance can be broken by presenting sources of altered antigen (e.g., homologous xenogeneic protein or protein expressed in insect cells). Immune responses induced with these sources of altered antigen reacted with various processed forms of native, syngeneic protein and could induce both tumor rejection and autoimmunity.Most antigens defined on human cancers are expressed both by malignant and normal cells (1-4). Studies of immune recognition of human cancer have shown that differentiation antigens (5), expressed by malignant cells and their normal cell counterparts, comprise a major group of tumor antigens recognized by the host (3). Thus, immunity against cancer in humans might be directed against self molecules. The question then arises how a host might convert from a state of immune tolerance or ignorance to immune response, to differentiation antigens on cancer, and whether such an immune response would be capable of rejecting tumors.The central work in the immune response to human cancer has been done in melanoma. A set of melanoma antigens is expressed both on malignant cells and normal melanocytes or related neuroectodermal cells (6-9). Three of these antigens are melanosomal membrane glycoproteins [tyrosinase͞albino protein, tyrosinase-related protein 1 (or gp75͞brown protein), and the gp100͞pMel 17͞silver protein], and one is an uncharacterized melanocyte-specific protein (MelanA͞MART-1 antigen) (10-23). Thus, one dominant set of antigens recognized on human melanoma are melanocyte differentiation antigens.Products of the brown locus expressed by melanocytes and melanoma are recognized by autoantibodies and T cells of persons with melanoma and are relevant tumor autoantigens (21,23). We have established a syngeneic model in C57BL͞6 mice to investigate immunogenicity of the brown locus protein and potential sequelae of autoimmunity (24). We show that (i) there is apparent tolerance to syngeneic ...
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