Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1

Scappaticci, Susi; Maraschio, P; Ciotto, N. Del; Fossati, Giuseppe; Zonta, A.; Fraccaro, M.

doi:10.1016/0165-4608(91)90057-2

Cited by 53 publications

(24 citation statements)

References 9 publications

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“…24,45 Most of these studies have been performed in fibroblasts or neuroendocrine cells, but patients' lymphocytes also exhibit chromosome instability and sensitivity to DNA-damaging agents. 46,47 Therefore, it is possible that both the defect in HSCs under replicative stress and the defect in B-cell differentiation relate to an inappropriate response to spontaneous or Rag-mediated double-strand DNA breaks, although further studies will be required to test this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells

Gan

Meyerson

et al. 2013

Blood

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Key Points• MLL1 does not require interaction with menin to maintain hematopoietic stem cell homeostasis.• Menin and MLL1 are both critical during B-cell differentiation, but largely through distinct pathways.Mixed Lineage Leukemia (MLL1) translocations encode fusion proteins retaining the N terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis and thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs); therefore, disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B cells, menin-or MLL1-regulated genes can be classified into 3 categories:(1) a relatively small group of coregulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukemia targeting agents.

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Section: Discussionmentioning

confidence: 99%

Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells

Gan

Meyerson

et al. 2013

Blood

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“…A number of studies have suggested that menin may have a role in DNA repair or maintenance of genome stability, based on findings of elevated frequencies of spontaneous or DNA damage-induced chromosome abnormalities in peripheral blood lymphocytes from multiple endocrine neoplasia type 1-affected individuals (7,30,53,59,60,65), raising the tantalizing possibility that menin has a role in maintaining the genomic integrity of the cell. Many proteins involved directly in repair processes, including RPA (15,22,43,51,55,58), form foci in response to agents that cause certain types of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

The 32-Kilodalton Subunit of Replication Protein A Interacts with Menin, the Product of the MEN1 Tumor Suppressor Gene

Sukhodolets

Hickman

Agarwal

et al. 2003

Molecular and Cellular Biology

111

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Menin is a 70-kDa protein encoded by MEN1, the tumor suppressor gene disrupted in multiple endocrine neoplasia type 1. In a yeast two-hybrid system based on reconstitution of Ras signaling, menin was found to interact with the 32-kDa subunit (RPA2) of replication protein A (RPA), a heterotrimeric protein required for DNA replication, recombination, and repair. The menin-RPA2 interaction was confirmed in a conventional yeast two-hybrid system and by direct interaction between purified proteins. Menin-RPA2 binding was inhibited by a number of menin missense mutations found in individuals with multiple endocrine neoplasia type 1, and the interacting regions were mapped to the N-terminal portion of menin and amino acids 43 to 171 of RPA2. This region of RPA2 contains a weak single-stranded DNA-binding domain, but menin had no detectable effect on RPA-DNA binding in vitro. Menin bound preferentially in vitro to free RPA2 rather than the RPA heterotrimer or a subcomplex consisting of RPA2 bound to the 14-kDa subunit (RPA3). However, the 70-kDa subunit (RPA1) was coprecipitated from HeLa cell extracts along with RPA2 by menin-specific antibodies, suggesting that menin binds to the RPA heterotrimer or a novel RPA1-RPA2-containing complex in vivo. This finding was consistent with the extensive overlap in the nuclear localization patterns of endogenous menin, RPA2, and RPA1 observed by immunofluorescence.Multiple endocrine neoplasia type 1 is a rare, autosomal dominant tumor syndrome, typically defined by the presence of tumors in at least two of the following three tissues: the parathyroid, enteropancreatic endocrine tissue, and the anterior pituitary (reviewed in reference 46). The human MEN1 gene was identified by positional cloning in 1997 (13) and shown to encode a 610-amino-acid product (menin) with predominantly nuclear localization (24). Loss of heterozygosity in the region containing the MEN1 locus has been observed in tumor tissue obtained from individuals with multiple endocrine neoplasia type 1 (39) and from mice with an engineered deletion in one of their Men1 alleles (16), predictive of a tumor suppressor function. This is supported by the detection of MEN1 frameshift or nonsense mutations in approximately 70% of human multiple endocrine neoplasia type 1 tumors (46). Menin overexpression has also been shown to diminish the tumorigenic phenotype of Ras-transformed NIH 3T3 cells (36), consistent with its putative tumor suppressor function. Knockout of both Men1 alleles in mice has been shown to result in embryonic lethality (16), suggesting that menin is also important for early development. However, the absence of significant homology to other proteins has complicated efforts to elucidate the function(s) of menin and/or the mechanisms of its tumor suppressor activity.A number of menin-interacting proteins have been identified in an effort to obtain clues about menin function, including the AP-1 transcription factor JunD (2), the putative tumor metastasis suppressor/nucleoside diphosphate kinase nm23 (54), the...

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“…Although the primary sequence of menin is highly conserved from fly to human, it does not bear obvious homology to known protein motifs, making it difficult to elucidate its biochemical function. Recent progress showed that menin regulates cell proliferation (5-7), apoptosis (8,9), and genome stability (10)(11)(12). Many of these functions rely on the ability of menin to regulate transcription of various genes, including cyclin-dependent kinase inhibitors and caspase 8 (9,13).…”

mentioning

confidence: 99%

The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

Chen

Yan

Keeshan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

171

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Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusionprotein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy. multiple endocrine neoplasia type 1 ͉ mixed lineage leukemia ͉ Men1 gene ͉ histone lysine methylation

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Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1

Cited by 53 publications

References 9 publications

Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells

Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells

The 32-Kilodalton Subunit of Replication Protein A Interacts with Menin, the Product of the MEN1 Tumor Suppressor Gene

The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

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