Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

Yoneda-Kato, Noriko; Fukuhara, Shirou; Kato, Jun‐ya

doi:10.1038/sj.onc.1202711

Cited by 37 publications

(39 citation statements)

References 44 publications

(30 reference statements)

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“…It is possible, likewise, that phosphorylation of the RSXSXP motif in Mlf1 promotes 14-3-3 binding, thereby sequestering the molecule in the cytoplasm and restricting its access to the nucleus. This model is consistent with primary localization of wild-type Mlf1 in the cytoplasm, with small amounts detected in punctate nuclear bodies (1,6,32). Importantly, although the NPM-MLF1 fusion protein is phosphorylated in vivo, it no longer binds 14-3-3 .…”

Section: Discussionsupporting

confidence: 65%

MADM, a Novel Adaptor Protein That Mediates Phosphorylation of the 14-3-3 Binding Site of Myeloid Leukemia Factor 1

Lim

Winteringham

Williams

et al. 2002

Journal of Biological Chemistry

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A yeast two-hybrid screen was conducted to identify binding partners of Mlf1, an oncoprotein recently identified in a translocation with nucleophosmin that causes acute myeloid leukemia. Two proteins isolated in this screen were 14-3-3 and a novel adaptor, Madm. Mlf1 contains a classic RSXSXP sequence for 14-3-3 binding and is associated with 14-3-3 via this phosphorylated motif. Madm co-immunoprecipitated with Mlf1 and colocalized in the cytoplasm. In addition, Madm recruited a serine kinase, which phosphorylated both Madm and Mlf1 including the RSXSXP motif. In contrast to wildtype Mlf1, the oncogenic fusion protein nucleophosmin (NPM)-MLF1 did not bind 14-3-3 , had altered Madm binding, and localized exclusively in the nucleus. Ectopic expression of Madm in M1 myeloid cells suppressed cytokine-induced differentiation unlike Mlf1, which promotes maturation. Because the Mlf1 binding region of Madm and its own dimerization domain overlapped, the levels of Madm and Mlf1 may affect complex formation and regulate differentiation. In summary, this study has identified two partner proteins of Mlf1 that may influence its subcellular localization and biological function.

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Section: Discussionsupporting

confidence: 65%

MADM, a Novel Adaptor Protein That Mediates Phosphorylation of the 14-3-3 Binding Site of Myeloid Leukemia Factor 1

Lim

Winteringham

Williams

et al. 2002

Journal of Biological Chemistry

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“…Notably, co-expression of BCL-2 rescued the fibroblasts from NPM-MLF1-mediated cell death. 49 In summary, we have shown that expression of BCL-2 family proteins and AR differ significantly between ALKϩ and ALKϪ ALCL of T/null lineage, and are not obviously related to PI. These findings further support the concept that ALKϩ ALCL of T/null lineage is a clinicopathological entity, distinct from ALKϪ ALCL, as has been suggested by others.…”

Section: Discussionmentioning

confidence: 98%

“…For instance, NPM-MLF1 is the chimeric product of t(3;5)(q25.1;q34), which is associated with myelodysplastic syndromes. In a recent paper by Yoneda-Kato and colleagues, 49 overexpression of NPM-MLF-1 was capable of inducing apoptosis in NIH3T3 mouse fibroblasts. This induction required the presence of an intact NPM dimerization domain.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of BCL-2 Family Proteins in ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma of T/Null-Cell Lineage

Rassidakis

Sarris

Herling

et al. 2001

The American Journal of Pathology

105

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Anaplastic large-cell lymphoma (ALCL) of T-or nullcell lineage, as defined in the revised European-American lymphoma classification, includes a subset of tumors that carry the t(2;5)(p23;q35) resulting in overexpression of anaplastic lymphoma kinase (ALK). Patients with ALK؉ ALCL are reported to have a better prognosis than patients with ALK؊ ALCL. Because the mechanisms for this survival difference are unknown, we investigated the hypothesis that apoptotic pathways may be involved. We therefore assessed expression levels of the anti-apoptotic proteins BCL-2 and BCL-XL and the pro-apoptotic proteins BAX and BCL-XS in T/nullcell ALCL using immunohistochemical methods and correlated the findings with ALK expression and apoptotic rate (AR), the latter assessed by a modified Tdtmediated dUTP nick-end labeling assay. ALK was de- Anaplastic large-cell lymphoma (ALCL) of T-or null-cell lineage, as defined in the revised European-American lymphoma classification, includes a subset of tumors that carry the t(2;5)(p23;q35). 1,2 The t(2;5) disrupts the nucleophosmin (NPM) gene at 5q35 and the anaplastic lymphoma kinase (ALK) gene at 2p23, generating a novel NPM-ALK gene consisting of the N-terminal portion of NPM fused to the cytoplasmic catalytic domain of ALK. 3,4 The t(2;5), its chimeric transcripts, and resulting overexpression of ALK protein have been detected in a variable proportion of ALCL, ranging from 12 to 80% in different series. [5][6][7][8][9][10] Variant translocations involving 2p23 also can cause overexpression of ALK. 11-14 Several studies have reported that patients with ALKϩ ALCL have better overall survival than patients with ALKϪ ALCL. [15][16][17] However, the underlying biological mechanisms for this survival difference are unknown.A number of proteins are involved in apoptosis, of which the BCL-2 protein family is best known. BCL-2, first identified by its involvement in the t(14;18) (q32;q21), 18,19 is a major negative regulator of apoptosis. The t(14;18) in follicular lymphoma results in BCL-2 overexpression, and represents the first example of oncogenesis mediated by decreased cell death. 20,21 A number of proteins have since been identified that share homology with conserved regions of BCL-2, the BCL-2 homology (BH) domains, and these proteins have either pro-apoptotic or anti-apoptotic activity in mammalian cells. 22 BAX, a 21-kd protein with significant homology clustered in the BH1 and BH2 regions, was the first of these proteins identified and is an important cell death agonist. 23 BCL-X, another gene homologous with BCL-2, gives rise to two alternatively spliced forms with opposite functions, long (BCL-XL) and short (BCL-XS). BCL-XL, like BCL-2, inhibits apoptosis, whereas BCL-XS is a cell death promoter. 24 -26 Many other BCL-2 family members have been described. 22 Pro-apoptotic and anti-apoptotic members of the BCL-2 family are capable of forming homodimers or heterodimers and their relative ratio acts as a rheostat for susceptibility to programmed cell death. 22,27 Supported in part b...

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“…The t(3;5)(q25;q34) translocation, seen in one of our patients, rearranges NPM gene with MLF1 gene and related to MDS progression to AML. 22 Translocations involving chromosome 1 were also observed in two cases of der(1;7)(q10;p10), as previously reported in MDS, 23 and in one case with t(1;2)(q21;q37) in our series, in which we identified a new HHL (human hornerin like) gene on 1q21 and showed that its overexpression might be related to MDS/AML transformation (manuscript prepared by YY Wang, SJ Chen et al).…”

Section: Discussionmentioning

confidence: 99%

Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries

et al. 2005

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Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

Cited by 37 publications

References 44 publications

MADM, a Novel Adaptor Protein That Mediates Phosphorylation of the 14-3-3 Binding Site of Myeloid Leukemia Factor 1

MADM, a Novel Adaptor Protein That Mediates Phosphorylation of the 14-3-3 Binding Site of Myeloid Leukemia Factor 1

Differential Expression of BCL-2 Family Proteins in ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma of T/Null-Cell Lineage

Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries

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