Delineating domains and functions of NUP98 contributing to the leukemogenic activity of NUP98-HOX fusions (original) (raw)
Related papers
Molecular and Cellular Biology, 2004
Abd-B Hox genes have been reported as fusion partners, indicating that they may have unique overlapping leukemogenic properties. To address this hypothesis, we engineered novel NUP98 fusions with Hox genes not previously identified as fusion partners: the Abd-B-like gene HOXA10 and two Antennepedia-like genes, HOXB3 and HOXB4. Notably, NUP98-HOXA10 and NUP98-HOXB3 but not NUP98-HOXB4 induced leukemia in a murine transplant model, which is consistent with the reported leukemogenic potential ability of HOXA10 and HOXB3 but not HOXB4. Thus, the ability of Hox genes to induce leukemia as NUP98 fusion partners, although apparently redundant for Abd-B-like activity, is not restricted to this group, but rather is determined by the intrinsic leukemogenic potential of the Hox partner. We also show that the potent leukemogenic activity of Abd-B-like Hox genes is correlated with their strong ability to block hematopoietic differentiation. Conversely, coexpression of the Hox cofactor Meis1 alleviated the requirement of a strong intrinsic Hox-transforming potential to induce leukemia. Our results support a model in which many if not all Hox genes can be leukemogenic and point to striking functional overlap not previously appreciated, presumably reflecting common regulated pathways.
NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice
The EMBO Journal, 2001
Here we describe hemopoietic chimeras serving as a mouse model for NUP98±HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98±HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98±HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our ®ndings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.
2003
Meis1 in concert with NUP98-HOXD13 leukemia-specific fusion gene Induction of acute myeloid leukemia in mice by the human http://bloodjournal.hematologylibrary.org/content/101/11/4529.full.html Updated information and services can be found at: (795 articles) Oncogenes and Tumor Suppressors (4212 articles) Neoplasia (3207 articles) Hematopoiesis and Stem Cells Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia
Blood, 2008
We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1+) as well as markers of the B-cell lineage (B220+). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, suc...
NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis
Cancer cell, 2016
The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion-driven leukemogenesis.
NUP98 Dysregulation in Myeloid Leukemogenesis
Annals of the New York Academy of Sciences, 2007
Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34 + cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five-to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBP␣. The HOXA9 component of the NUP98-HOXA9 fusion protein was protected from cullin-4Amediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34 + cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the
Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation
Cancer Research, 2006
The t(7;11)(p15;p15) translocation, observed in acute myelogenous leukemia and myelodysplastic syndrome, generates a chimeric gene where the 5 ¶ portion of the sequence encoding the human nucleoporin NUP98 protein is fused to the 3 ¶ region of HOXA9. Here, we show that retroviral-mediated enforced expression of the NUP98-HOXA9 fusion protein in cord bloodderived CD34 + cells confers a proliferative advantage in both cytokine-stimulated suspension cultures and stromal coculture. This advantage is reflected in the selective expansion of hematopoietic stem cells as measured in vitro by cobblestone area-forming cell assays and in vivo by competitive repopulation of nonobese diabetic/severe combined immunodeficient mice. NUP98-HOXA9 expression inhibited erythroid progenitor differentiation and delayed neutrophil maturation in transduced progenitors but strongly enhanced their serial replating efficiency. Analysis of the transcriptosome of transduced cells revealed up-regulation of several homeobox genes of the A and B cluster as well as of Meis1 and Pim-1 and down-modulation of globin genes and of CAAT/enhancer binding protein A. The latter gene, when coexpressed with NUP98-HOXA9, reversed the enhanced proliferation of transduced CD34 + cells. Unlike HOXA9, the NUP98-HOXA9 fusion was protected from ubiquitination mediated by Cullin-4A and subsequent proteasome-dependent degradation. The resulting protein stabilization may contribute to the leukemogenic activity of the fusion protein. (Cancer Res 2006; 66(24): 11781-91) Requests for reprints: Malcolm A.S. Moore,
Leukemia, 2005
Hox genes have been identified in chromosomal translocations involving the nucleoporin gene NUP98. Though the resulting chimeric proteins directly participate in the development of leukemia, the long latency and monoclonal nature of the disease support the requirement for secondary mutation(s), such as those leading to overexpression of Meis1. Models to identify such events and to study leukemic progression are rare and labor intensive. Herein, we took advantage of the strong transforming potential of NUP98-HOXD13 or NUP98-HOXA10 to establish preleukemic myeloid lines from bone marrow cells that faithfully replicate the first step of Hox-induced leukemogenesis. These lines contain early granulomonocytic progenitors with extensive in vitro self-renewal capacity, short-term myeloid repopulating activity and low propensity for spontaneous leukemic conversion. We exploit such lines to show that Meis1 efficiently induces their leukemic progression and demonstrate a high frequency of preleukemic cells in the cultures. Furthermore, we document that the leukemogenic potential of Meis1 is independent of its direct binding to DNA and likely reflects its ability to increase the repopulating capacity of the preleukemic cells by increasing their selfrenewal/proliferative capacity. The availability of lines with repopulating potential and capacity for leukemic conversion should open new avenues for understanding progression of Hox-mediated acute myeloid leukemia.
Blood Advances, 2019
• NUP98-HBO1 induces clinically relevant diversity of CMML phenotypes, such as increased classical monocytes, myelodysplasia, and cachexia. • CMML-specific transcriptional signature is induced through aberrant histone acetylation. Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/ progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115 1 Ly6C high monocytes (an equivalent subpopulation to human classical CD14 1 CD16 2 monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1-mediated transcriptional signature in human CD34 1 cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential.
NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights
Blood, 2011
Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to g...