St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

Transforming potential of the c-fms proto-oncogene (CSF-1 receptor)

Abstract: The c-fms proto-oncogene encodes a transmembrane glycoprotein that is probably identical to the receptor for the macrophage colony stimulating factor, CSF-11. Forty C-terminal amino acids of the normal receptor are replaced by 11 unrelated residues in the feline v-fms oncogene product2, deleting a C-terminal tyrosine residue (Tyr969) whose phosphorylation might negatively regulate the receptor kinase activity3–5. We show that the human c-fms gene stimulates growth of mouse NIH 3T3 cells in agar in response to human recombinant CSF-1, indicating that receptor transduction is sufficient to induce a CSF-1 responsive phenotype. Although cells transfected with c-fms genes containing either Tyr969 or Phe969 were not transformed, cotransfection of these genes with CSF-1 complementary DNA induced transformation, with c-fms(Phe969) showing significantly more activity than c-fms(Tyr969). In the absence of CSF-1, chimaeric v-fms/c-fms genes encoding the wild-type c-fms C terminus were poorly transforming, whereas chimaeras bearing Phe969 were as transforming as v-fms. Thus, the Phe969 mutation, although not in itself sufficient to induce transformation, activates the oncogenic potential of c-fms in association with an endogenous ligand or in conjunction with mutations elsewhere in the c-fms gene that confer ligand-independent signals for growth.

CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity

Abstract: An expanding subgroup of chromosomal translocation-generated oncoproteins in human acute myeloid leukemias (AML) involve the FG repeat-containing nuclear pore complex (NPC) proteins NUP98 (39) and CAN/NUP214 (13, 22). The NUP98 gene is found at the breakpoints of two distinct chromosomal rearrangements: t(7;11)(p15;p15) (7, 18, 33), and inv(11)(p15;q22) (2), which link NUP98 to the class I homeotic transcription factor HOXA9 and the putative RNA helicase DDX10, respectively. In each rearrangement, the chromosomal breakpoints are located within two flanking introns of the NUP98 gene that separate the FG repeat-rich N terminus of NUP98 from its C terminus, which contains a ribonucleoprotein (RNP)-binding motif (39). Although each translocation generates two reciprocal chimeric products, only those driven by the NUP98 promoter and containing the FG repeat region are predicted to mediate leukemogenesis (2, 7, 33). Another nucleoporin gene, CAN/NUP214, is found at the breakpoint of two independent chromosomal rearrangements: t(6;9)(p23;q34), which fuses CAN/NUP214 to DEK (49), and inv(9;9)(q34;q34), which links it to SET (50). The leukemia-specific transcripts, DEK-CAN/NUP214 and SET-CAN/NUP214, both encode nuclear fusion proteins. The proteins contain identical C-terminal portions of CAN/NUP214, including its FG repeat-rich region, and a coiled-coil domain (13, 22). DEK and SET are both nuclear proteins that have no sequence similarity other than the presence of acidic motifs that may participate in DNA binding (13, 14, 31). The involvement of two FG repeat-containing nucleoporins in multiple translocations associated with human leukemia raises intriguing questions about their role in leukemogenesis. In particular, the consistent presence of FG repeat regions suggests that such domains could serve a common function in the transformation of hematopoietic cells. Many of the known components of the NPC have regions rich in FXFG, GLFG and/or FG repeats (amino acids are given in single-letter code, with X indicating any amino acid). Such repeats (called FG for simplicity) are presumed contact sites for soluble nucleocytoplasmic transport factors carrying different kinds of cargo; however, their precise functions in vivo remain to be determined (35, 36). HOXA9, expressed in both the primitive pluripotent precursors and the myeloid progenitors of human bone marrow (42), is the only nucleoporin fusion partner with an established physiological role in hematopoietic development. HOXA9 knockout mice have multiple hematopoietic defects, including reduced numbers of peripheral blood granulocytes and lymphocytes, as well as myeloid and pre-B-cell progenitors, and their spleens and thymuses are smaller than normal (25). Besides its involvement in t(7;11)-mediated myeloid leukemogenesis, HOXA9 has been implicated in the formation of myeloid leukemias in the BXH-2 strain of mice (29). BXH-2 mice carry an endogenous murine leukemia virus that acts as a viral mutagen predisposing the animals to myeloid malignancies (4, 5). In this experimental tumor model, about 3% of all leukemias in BXH-2 mice display proviral activation of HOXA9 (34). Constitutive expression of HOXA9 alone is not sufficient for efficient transformation of murine hematopoietic cells; it requires coexpression of MEIS1 (23, 34), a PBX1-related divergent homeodomain-containing protein that cooperatively binds DNA with HOXA9 in vitro (44). In this study, we show that the t(7;11)-derived fusion gene generates two chimeric proteins via alternative splicing within NUP98. Investigation of the structural and functional regions of the chimeric NUP98-HOXA9 proteins demonstrated that HOXA9-mediated DNA binding and interaction with PBX are essential for transformation of NIH 3T3 fibroblasts. In both chimeras, the NUP98 portions contained very potent transcription activation domains, which replace a strong transcriptional repressor domain within the amino-terminal half HOXA9. Interestingly, the transcriptional coactivators CREB binding protein (CBP) and potentially p300 interacted and functionally cooperated with the NUP98 FG-repeat-rich portions. Abbrogation of NUP98-HOXA9-mediated transformation corresponded to the loss of NUP98-mediated transcriptional activity and CBP binding. Thus, NUP98-HOXA9 seems to recruit CBP/p300 as part of its oncogenic mechanism. Because CBP and p300 are coactivators for a number of gene-specific transcription factors, they could also be critical accessory factors for other fusion proteins that deregulate transcription.

Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia

Abstract: T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a poor prognosis and no available targeted therapies; now two histone H3 lysine 27 demethylases, JMJD3 and UTX, are shown to have contrasting roles in human T-ALL cells and a mouse model of the disease, and a small molecule demethylase inhibitor is found to inhibit the growth of T-ALL cell lines, introducing a potential therapeutic avenue for acute leukaemia. Two histone H3 lysine 27 demethylases, JMJD3 and UTX, are shown here to have contrasting roles in human T-cell acute lymphoblastic leukaemia (T-ALL) cells and a mouse model of the disease. JMJD3 is overexpressed in T-ALL and essential for initiation and maintenance of disease, whereas UTX is a target of inactivating mutations in human T-ALL and acts a tumour suppressor. A small-molecule demethylase inhibitor inhibits the growth of T-ALL cell lines, introducing a potential therapeutic avenue for an acute leukemia that has a poor prognosis and no currently available targeted therapies. T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders1, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified2,3; however, ‘epigenetic’ drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL4. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.