Nucleoporins and nucleocytoplasmic transport in hematologic malignancies.

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Review

Nucleoporins and nucleocytoplasmic transport in hematologic malignancies Akiko Takeda, Nabeel R. Yaseen ∗ Department of Pathology and Immunology, Washington University in St. Louis, United States

a r t i c l e

i n f o

Keywords: Nucleoporin NUP98 NUP214 CRM1 XPO1 Leukemia Acute myeloid leukemia Acute lymphoblastic leukemia Nuclear export Nucleocytoplasmic transport

a b s t r a c t Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins [1] (Fig. 1). Among the proteins that are known to be part of such oncogenic fusions, are two nucleoporins, NUP98 and NUP214. Nucleoporins are protein components of the nuclear pore complex (NPC). In conjunction with soluble shuttling carrier proteins (karyopherins), they play important roles in the nucleocytoplasmic transport of macromolecules [2–6]. Components of the nucleocytoplasmic transport machinery also play pivotal roles in other cellular processes such as mitosis and transcription [2–6]. Oncogenic nucleoporin fusions have been described in several types of hematologic malignancies, most commonly acute myeloid leukemia (AML), but also including myelodysplastic syndromes (MDS) and T-cell acute lymphoblastic leukemia (T-ALL). AML is a malignant proliferation of myeloid precursors characterized by failure of myeloid differentiation with accumulation of primitive cells (blasts) in the bone marrow and blood [7]. Myeloid malignancies

∗ Corresponding author at: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8118, St. Louis, MO 63110, United States. Tel.: +1 314 362 0306. E-mail addresses: [email protected] (A. Takeda), [email protected] (N.R. Yaseen).

associated with NUP98 fusions often arise as a complication of prior chemotherapy with topoisomerase II inhibitors [8]. Nucleoporinassociated malignancies tend to occur at a younger age and have a poor clinical outcome [8–27].

2. Oncogenic NUP98 fusions At least 29 NUP98 fusions have been reported in hematopoietic malignancies, mostly AML, but also including T-ALL and MDS [8–22,28–30] (Table 1). In most cases the breakpoints occur in introns 11–13 of NUP98, resulting in fusion of the N-terminal region of NUP98 that is rich in phenylalanine–glycine (FG) repeats to one of 29 different proteins [30]. Many of the NUP98 fusion partners are transcription factors of the homeobox family; the prototype of such fusions is NUP98-HOXA9 [31,32]. The overall incidence of NUP98 fusions is not clear and there is evidence that it may vary by geographical region [30]. For example, the vast majority of NUP98HOXA9 fusions have been reported in patients from the Far East [8,26,33,34]. NUP98-NSD1 has been reported in 16.1% of pediatric and 2.3% of adult cytogenetically normal AML [35]. NUP98-JARID1A was identified in 10.5% of cases of pediatric acute megakaryoblastic leukemia (a subset of AML) [36]. A study from Taiwan identified NUP98-HOXA9 in 2.23% of adult AML patients [26]. NUP98 fusions cause aberrant differentiation and increased proliferation when expressed in primary human hematopoietic

http://dx.doi.org/10.1016/j.semcancer.2014.02.009 1044-579X/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Takeda A, Yaseen NR. Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Semin Cancer Biol (2014), http://dx.doi.org/10.1016/j.semcancer.2014.02.009

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t(6;9)(p23;q34)

Normal

cells [37–40]. When introduced into mice by transplantation or transgenically, they cause myeloproliferation, MDS and AML with relatively long latency and variable penetrance, suggesting that additional cooperating oncogenic events are needed for the development of full-blown leukemia [16,41–49]. This notion is supported by clinical data as well as in vivo studies in mice. NUP98 rearrangements have been described in patients with BCR-ABL1positive chronic myelogenous leukemia who developed blast crisis, which is a form of AML, suggesting that NUP98 fusions can cooperate with BCR-ABL1 in causing AML [50]. Further, patients with hematologic malignancies associated with NUP98 fusions have an increased incidence of additional mutations such as FLT3 internal tandem duplications (FLT3-ITD), KIT, WT1 and KRAS [26,35,51]. Several mouse studies have shown that oncogenes, including Meis1, FLT3, and BCR-ABL1, can cooperate with NUP98 fusions and enhance their leukemogenic potential [41,42,47,52–58]. 3. Oncogenic NUP214 fusions

Chr. 6

Chr. 9

der(6)

der(9)

Fig. 1. Schematic of the t(6;9)(p23;q34) chromosomal rearrangement that results in the DEK-NUP214 oncogenic fusion. On the left are normal chromosomes 6 and 9; the Giemsa banding pattern is shown in brown and blue, respectively. The centromeres are shown in red and the non-centromeric heterochromatin of chromosome 9 is shown in pink. On the right are shown the derivative chromosomes 6 and 9 that result from the t(6;9)(p23;q34) chromosomal rearrangement. The arrowheads indicate the chromosomal breakpoints. Table 1 Nucleoporin gene rearrangements in hematologic malignancies. AML = acute myeloid leukemia, CML-BC = chronic myelogenous leukemia in blast crisis, MDS = myelodysplastic syndrome, t-AML = therapy-related acute myeloid leukemia, t-MDS = therapy-related myelodysplastic syndrome, APL = acute promyelocytic leukemia, T-ALL = T-cell Acute lymphoblastic leukemia, B-ALL = B-cell acute lymphoblastic leukemia, and AUL = acute undifferentiated leukemia. Rearrangement

Fusion transcript

Disease

NUP98 t(7;11)(p15;p15)

NUP98-HOXA9

t(7;11)(p15;p15) t(7;11)(p15;p15) t(11;12)(p15;q13) t(11;12)(p15;q13) t(2;11)(q35;p15) t(2;11)(q31;p15) t(1;11)(q23;p15) t(9;11)(q34;p15) t(10;11)(q23;p15) inv(11)(p15;q22) t(11;20)(p15;q11) t(9;11)(p22;p15) t(5;11)(q31;p15) t(8;11)(p11.2;p15) t(3;11)(p24;p15) Complex (12p13) t(11;17)(p15;p13) Complex (3p25) t(6;11)(q24.1;p15.5)

NUP98-HOXA11 NUP98-HOXA13 NUP98-HOXC11 NUP98-HOXC13 NUP98-HOXD11 NUP98-HOXD13 NUP98-PMX1 NUP98-PRRX2 NUP98-HHEX NUP98-DDX10 NUP98-TOP1 NUP98-PSIP1 NUP98-NSD1 NUP98-NSD3 NUP98-TOP2B NUP98-JARID1A NUP98-PHF23 NUP98-ANKRD28 NUP98-CCDC28A

Complex (3q29) t(11;18)(p15;q12) t(4;11)(q21;p15) t(10;11)(q25;p15) t(X;11)(q28;p15) t(3;11)(q12;p15) inv(11)(p15q23) t(11;12)(p15;q13) t(3;11)(p11;p15)

NUP98-IQCG NUP98-SETBP1 NUP98-RAP1GDS1 NUP98-Adducin 3 NUP98-HMGB3 NUP98-LOC348801 NUP98-MLL NUP98-RARG NUP98-POU1F1

AML/MDS, t-AML/MDS, CML CML-BC AML, MDS AML AML Pediatric AML AML, t-AML AML, t-MDS/AML t-AML AML AML, MDS, CML AML, t-MDS AML, MDS Pediatric AML AML AML (Monoblastic) AML (Megakaryoblastic) AML MDS/AML AML (Megakaryoblastic), T-ALL Biphenotypic T-ALL/AML Pediatric T-ALL Adult T-ALL T-ALL t-AML AML AML APL t-AML

DEK-NUP214 SET-NUP214 SQSTM1-NUP214 NUP214-ABL1

AML T-ALL, AML, AUL T-ALL T-ALL, B-ALL

NUP214 t(6;9)(p23;q34) del(9)(q34) der(5)t(5;9)(q35;q34) Amplified episomes

NUP214 was the first nucleoporin to be implicated in the pathogenesis of hematologic malignancies [59]. The translocation t(6;9)(p23;q34) (Fig. 1) results in a DEK-NUP214 fusion and defines a specific subcategory of AML under the most recent World Health Organization classification of AML [23]. This subtype of AML is characterized by basophilia, poor clinical outcome, and a high incidence of FLT3-ITD [23,60–62]. The breakpoints always occur within the same introns of both DEK and NUP214, resulting in an invariant fusion protein that includes the C-terminal FG repeat region of NUP214 [25,63]. SET-NUP214 is a fusion between exon 7 of SET and exon 18 of NUP214 that results from del(9)(q34). It is associated with T-ALL and less frequently with AML and acute undifferentiated leukemia [64–70]. Most reported cases in the literature are from the Far East [64–70]. Fusion SQSTM1-NUP214 has been reported in a patient with refractory T-ALL [71]. Recently, a NUP214-ABL1 fusion was described in a series of patients with T-ALL [72,73]. This fusion is cytogenetically cryptic and is often located on amplified episomes. In contrast to other NUP214 fusions, NUP214-ABL1 fusions contain an N-terminal portion of NUP214 that includes some but not all of the FG repeats. This fusion has also been described in B cell acute lymphoblastic leukemia [74,75]. In T-ALL, NUP214-ABL1 is usually associated with rearrangement and/or overexpression of TLX1 or TLX3 and/or deletion of the tumor suppressor CDKN2a [72,76]. In some patients there are more cells with abnormalities of these genes than with NUP214-ABL1, suggesting that the latter is a secondary mutation [76]. In transduction/transplantation studies, DEK-NUP214 induced AML in mice with low penetrance and long latency; the penetrance was enhanced and the latency shortened by enriching the transduced population for long-term hematopoietic stem cells [77]. Conflicting data have been reported on the effects of DEK-NUP214 in human myeloid cell lines. In one study DEK-NUP214 caused mild growth inhibition in the myeloid cell line U937 [78], whereas in a subsequent study DEK-NUP214 was found to enhance proliferation of U937 and another myeloid cell line, PL-21, through upregulation of the mTOR pathway [79]. SET-NUP214 transgenic mice showed some abnormalities in hematopoietic differentiation and expansion of early precursors but no clear-cut leukemic phenotype [80,81]. 4. Subcellular localization of nucleoporin fusions Normally, NUP214 is present primarily on the cytoplasmic face of the NPC [59], whereas NUP98 is present on both the nuclear and cytoplasmic sides of the NPC as well as within the nucleus [82–84].


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CRM1

Cytoplasm

NES

Ran GDP

3

B Cytoplasm

Txn Factor

NUP214 CRM1

NES RanGTP

NPC

NPC

NPC

NPC

Txn Factor NUP98 CRM1

NES RanGTP

Txn Factor

NUP98 CRM1

NES RanGTP

Txn Factor DNA

?

NUP98 CRM1

NES RanGTP

Txn Factor DNA

HOXA9

?

Fig. 2. CRM1-mediated nuclear export and hypothetical role of CRM1 in transcription. (A) CRM1 binds to NES-bearing cargo, such as transcription factors, in the presence of RanGTP. NUP98 facilitates the transport of the export complex by interacting with the NPC through its C-terminal portion. The export complex also interacts with NUP214 on its way toward the cytoplasm. On the cytoplasmic side of the NPC, GTP hydrolysis results in conversion of RanGTP to RanGDP, which results in dissociation of the export complex and release of the cargo into the cytoplasm. In the pink oval is shown a hypothetical model for a role of the export complex containing a transcription factor, CRM1, NUP98, and RanGTP in transcription. Under normal conditions, this complex would be in equilibrium between DNA binding and export. (B) In leukemias associated with a NUP98 fusion, the C-terminal portion of NUP98 is lost, precluding its interaction with the NPC and resulting in sequestration of the export complex inside the nucleus. According to the suggested model, the equilibrium is shifted in favor of the export complex remaining bound to DNA, resulting in increased transcriptional activity.

In both DEK-NUP214 and SET-NUP214, the NPC-targeting coiled-coil domains of NUP214 are lost, resulting intranuclear localization of the fusion protein [85]. In contrast, NUP214-ABL1 retains the coiled-coil domains resulting in its localization to the NPC [86]. NPC localization appears necessary for the transforming ability of NUP214-ABL1 [86]. The NPC-targeting sequences of NUP98 reside in its C-terminal portion [87–89], which is lost in oncogenic NUP98 fusions. As a result, NUP98 fusions do not localize to the nuclear rim and are instead localized inside the nucleus in a punctate distribution that has been observed both in transduced primary human cells [40,90] and in cells from patients with AML [35,91].

including transcription factors [90]. Similarly, SET-NUP214 binds to CRM1, causes aberrant punctate intranuclear localization of CRM1, and inhibits CRM1-mediated nuclear protein export [104]. Further, our unpublished data show that the oncogenic fusion DEK-NUP214 similarly interacts with, and mislocalizes, CRM1. These findings raise the possibility that nuclear retention of transcriptional regulators that are normally exported from the nucleus by CRM1 may contribute to the dysregulation of transcription by nucleoporin fusions. There is evidence that NUP98 and NUP214 are involved in RNA export and protein import [105–118]. However there is no evidence to date that nucleoporin fusions interfere with these processes.

5. Nucleoporins and nucleocytoplasmic transport

6. Nucleoporins in mitosis

The mammalian NPC is a very large structure with 8-fold symmetry that consists of approximately 30 nucleoporins, each present in multiple copies. It is the gateway for the exchange of macromolecules between the nucleus and the cytoplasm [2,92–95]. In addition to nucleoporins, nucleocytoplasmic transport generally requires carrier proteins that bind to cargo and facilitate its transport through the NPC. Different carriers mediate the import and export of different subsets of proteins and RNAs [6,93,96]. A number of nucleoporins, including NUP98 and NUP214, contain FG repeats and function in nucleocytoplasmic transport by interacting with these carriers [93]. Both NUP98 and NUP214 play a role in the nuclear export of proteins by binding to the nuclear export carrier CRM1 (XPO1) [6,90,97–101] (Fig. 2A). CRM1 recognizes leucine-rich nuclear export sequences (NESs) on cargo proteins and binds to them in the presence of the GTP-bound form of the small GTPase Ran (Ran-GTP). The export complex passes through the NPC out to the cytoplasm where GTP hydrolysis results in dissociation of the cargo from CRM1 [102,103] (Fig. 2A). NUP98 fusions bind to CRM1 resulting in its mislocalization to punctate intranuclear domains. This is associated with a block of CRM1-mediated nuclear export of proteins

Recent evidence indicates that some nucleoporins, in addition to their roles in nucleocytoplasmic transport, play significant roles during mitosis. An extensive review of the roles of nucleoporins in mitosis has been published recently [4]. Here, we will focus on recent data pertaining to the roles of NUP98, NUP214, and oncogenic nucleoporin fusions in mitosis. Phosphorylation of NUP98 is an important rate-limiting step in NPC disassembly during mitosis [119]. Nup98 regulates bipolar spindle assembly through association of its C-terminal domain with microtubules [120]. Nup98, in complex with the mRNA export factor Rae1, is one of the modulators of mitotic spindle assembly checkpoint (SAC). The Nup98/Rae1 complex regulates timely destruction of securin by the anaphase-promoting complex (APC), and combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin [121]. RNAi-mediated knockdown of NUP98 similarly causes severe chromosome segregation defects as well as disrupted RAE1 expression and localization [122]. Nup214 and Nup88, that normally form a complex at the NPC, are localized at the spindle during mitosis [123]. Other nucleoporins also play critical roles in mitosis through interactions with a large


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network of proteins at both the kinetochore and the centrosome [124,125]. There is some evidence that NUP98 fusions may play an aberrant role in mitosis. Expression of NUP98-HOXA9 causes downregulation and mislocalization of RAE1 protein [122]. NUP98homeodomain fusions interact with endogenous NUP98 during interphase but during mitosis they localize to kinetochores and chromosome arms without endogenous NUP98 [126]. The network that connects nucleoporins to kinetochores and centrosomes includes the cytoplasmic dynein motor complex [124,125,127]. Interestingly, one dynein light chain, DYNLT1, has been found to specifically associate with NUP98-HOXA9 as well as wildtype NUP98 and other FG repeat-containing nucleoporins, and to play a role in the dysregulation of gene expression and induction of hematopoietic cell proliferation by NUP98-HOXA9 [128]. These data raise the possibility that, in patients with NUP98 rearrangements, oncogenic NUP98 fusions and deficiency of wild-type NUP98 may contribute to oncogenic transformation by causing defective chromosomal segregation. However, it remains to be determined whether patient cells with NUP98 fusions express less endogenous NUP98 and whether they show abnormalities in chromosomal segregation. In addition to nucleoporins, soluble carrier proteins involved in nucleocytoplasmic transport, including karyopherin ␤1 (importin ␤1) and CRM1, as well as the small GTPase Ran, play an important role in mitosis [124]. CRM1, independently from its well-known role in nuclear export, appears to be involved in maintenance of centrosome integrity and microtubule nucleation from kinetochores. It is of particular interest because one of its inhibitors, KPT-330 [129], is currently in clinical trials for the treatment of hematopoietic malignancies [130]. A fraction of CRM1 localizes to the centrosomes and is involved in maintaining centrosome integrity [131]. The mechanism by which CRM1 plays this role is not clearly understood. It is possible that CRM1 cargoes such as nucleophosmin (NPM1), by binding to CRM1 via their NES, play a role in maintaining proper centrosome duplication [132,133]. CRM1 is also found at the kinetochore during mitosis and it recruits NUP358 (RanBP2) and RanGAP1 to mitotic kinetochores in the presence of RanGTP [134]. CRM1 is phosphorylated by CDK1/Cyclin B at serine 391 during mitosis, which enhances its RanGTP-dependent interaction with RanGAP1-RanBP2 and promotes their recruitment to the mitotic spindle for proper assembly [135]. Another important role of CRM1 in mitosis is to tether the chromosomal passenger complex (CPC) to the centromere by interacting with the NES of survivin in early prophase [136]. The CPC is required at various stages during mitosis and cytokinesis [137]. As discussed above, NUP98 and NUP214 oncogenic fusions interact with CRM1 resulting in its mislocalization. These interactions may play a role in oncogenesis by perturbing the normal mitotic process.

7. Nucleoporins in transcription NUP98 is a mobile nucleoporin whose mobility is linked to ongoing transcriptional activity [83]. The first evidence for a direct transcriptional role of nucleoporins was that the FG repeat regions of NUP98 and NUP214 can recruit CBP/p300 and act as transactivating domains when linked to a GAL4 DNA-binding domain [138]. The FG repeat region of NUP98 can recruit CBP/p300 to activate transcription or HDAC1 to repress transcription [138,139]. Data from both human and Drosophila cells showed that wild-type nucleoporins, including NUP98, bind to chromatin at transcriptionally active genes and regulate transcription [140–144]. Binding of NUP98 to gene regulatory elements was demonstrated in human HeLa cells where it is required for IFN␥-mediated transcriptional memory through dimethylation of H3K4 [145]. At least part of the

chromatin binding activity of NUP98 resides in its FG repeat region, and this binding appears to preferentially correlate with increased gene expression [143]. Similarly, the FG repeat-containing nucleoporin NUP153 and another nucleoporin, Mtor/TPR, have been shown to interact with the dosage compensation complex (DCC) containing MSL proteins and the MOF histone acetyl transferase and are required for the targeting of MSL proteins to the X chromosome [140]. The DCC is responsible for acetylation of H4K16 on the male X chromosome resulting in chromatin decondensation and increased gene expression [146]. Depletion of NUP153 resulted in downregulation of dosage-compensated genes [140]. These findings were later expanded to show genome-wide association of NUP153 and Mtor with chromatin at regions that are enriched for active genes, RNA polymerase II binding, and H4K16 acetylation [144]. The mechanisms by which nucleoporins are targeted to chromatin, however, remain unclear. All NUP98 fusions, and most NUP214 fusions include the FG repeats that can regulate transcription by recruiting coactivators and corepressors as discussed above. In a number of NUP98 fusions, the fusion partner supplies a DNA-binding domain. At least 10 NUP98 rearrangements result in fusion of NUP98 to a homeobox transcription factor, and the fusion product always includes the DNA-binding homeodomain [30]. There is evidence that in these cases the homeodomain is required for DNA binding, dysregulated transcription, and leukemic transformation [38,41,42,44,47,48,138,139,147–150]. Other NUP98 fusion partners contain chromatin-interacting motifs. NUP98-JARID1A and NUP98-PHF23 use their PHD fingers to bind to H3K4me3 and upregulate expression of HOXA genes [45]. Similarly, NUP98-NSD1 was shown to bind to the HOXA locus and upregulate the expression of HOX transcription factors through maintenance of H3K36 methylation and histone acetylation [44]. The region of NSD1 encompassing the 5th PHD finger (PHD5) and the adjacent Cys-His-rich domain (C5HCH) is required for binding to the HOXA locus [44]. While the chromatin component bound by the PHD5-C5HCH motif of NSD1 is not known, the corresponding PHD5-C5HCH motif of NSD3 binds to unmodified H3K4 and trimethylated H3K9 through the PHD5 domain [151]. Of note, a NUP98-NSD3 fusion has been reported in AML and MDS [152,153]. On the other hand, there is no evidence that the remaining nucleoporin fusions (Table 1) contain a DNA-binding domain. This raises the question of how these fusions, such as NUP98-DDX10 [40], can dysregulate transcription. One possibility, discussed above, is interference with the nuclear export of transcription factors such as NF␬B [90]. Another possibility is that the oncogenic fusion can be targeted to chromatin through the nucleoporin moiety, regardless of the fusion partner. This possibility is supported by the findings described above showing that wild type nucleoporins associate with chromatin. However, the mechanism by which NUP98 and other nucleoporins are targeted to chromatin remains unclear. One possible model is illustrated in Fig. 2A. NUP98 binds to CRM1, which in turn is known to bind numerous transcription factors in its capacity as a nuclear export carrier [98,154–161]. It is possible that these interactions also occur in the context of chromatin, with CRM1 and its associated transcription factors cooperating with NUP98 in binding to chromatin and transcriptional regulation (Fig. 2A). With NUP98 fusions, on the other hand, the C-terminal portion of NUP98, which is responsible for interaction with the NPC, is lost resulting in a block of CRM1-mediated nuclear export [90]. Under the proposed model, the export complex would remain in the nucleus, favoring its association with chromatin, leading to increased transcriptional activity (Fig. 2B). As discussed above, NUP214 and its fusions also bind to CRM1 and inhibit CRM1-mediated nuclear export. It is possible that NUP214 regulates transcription and that its fusions dysregulate transcription by mechanisms similar to those proposed in Fig. 2.




8. Inhibitors of nuclear export Several inhibitors of CRM1-mediated nuclear export are under development for the treatment of cancer [102,130,162,163]. These inhibitors generally act by binding to the cysteine residue 528 at the active site of CRM1, which disrupts the interaction of CRM1 with its cargo and results in a block of CRM1-mediated nuclear export [102]. Of the many CRM1 inhibitors under development, KPT-330 is currently in Phase 1 trials in solid tumors as well as in hematologic malignancies, including AML [130,163]. Inhibition of the nuclear export of tumor suppressors such as p53, APC, and retinoblastoma has been suggested as a possible mechanism for the antitumor activity of CRM1 inhibitors [102,164]. The roles of CRM1 in mitosis may provide additional targets for CRM1 inhibitors in cancer therapy. For example, the CRM1 inhibitor leptomycin B (LMB) prevents the recruitment of NUP358/RanBP2 to the kinetochore and disrupts mitotic progression and chromosome segregation [134]. On the other hand, if CRM1 indeed cooperates with nucleoporin fusions in dysregulating transcription as proposed in the model shown in Fig. 2B, patients with nucleoporin fusions may respond preferentially to treatment with CRM1 inhibitors. In addition, a subset of AML is characterized by mutations in the nucleolar protein nucleophosmin (NPM1) that result in the formation of an extra NES recognized by CRM1 [165]. This results in aberrant cytoplasmic localization of NPM1 [166] that is thought to contribute to leukemogenesis [167]. It has been shown that CRM1 inhibition can reverse the aberrant cytoplasmic localization of mutant NPM1 [90]. It would be of great interest to determine whether CRM1 inhibitors are effective in treating patients with nucleoporin fusions and NPM1 mutations. Conflict of interest Our laboratory has received research funding from Karyopharm Therapeutics, which develops nuclear export inhibitors for clinical use. References [1] Scandura JM, Boccuni P, Cammenga J, Nimer SD. Transcription factor fusions in acute leukemia: variations on a theme. Oncogene 2002;21:3422–44. [2] Raices M, D’Angelo MA. Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Biol 2012;13:687–99. [3] Chatel G, Fahrenkrog B. Dynamics and diverse functions of nuclear pore complex proteins. Nucleus 2012;3:162–71. [4] Chatel G, Fahrenkrog B. Nucleoporins: leaving the nuclear pore complex for a successful mitosis. Cell Signal 2011;23:1555–62. [5] Capelson M, Doucet C, Hetzer MW. Nuclear pore complexes: guardians of the nuclear genome. Cold Spring Harb Symp Quant Biol 2010;75:585–97. [6] Hutten S, Kehlenbach RH. CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol 2007;17:193–201. [7] Bain BJ. Leukaemia diagnosis. 2nd ed. London: Blackwell Science; 1999. [8] Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N, et al. NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogenetique Hematologique. Leukemia 2006;20:696–706. [9] Tosi S, Ballabio E, Teigler-Schlegel A, Boultwood J, Bruch J, Harbott J. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia. Genes Chromosomes Cancer 2005;44:225–32. [10] Nebral K, Schmidt HH, Haas OA, Strehl S. NUP98 Is Fused to Topoisomerase (DNA) II{beta} 180 kDa (TOP2B) in a patient with acute myeloid leukemia with a new t(3;11)(p24;p15). Clin Cancer Res 2005;11:6489–94. [11] van Zutven LJ, Onen E, Velthuizen SC, van Drunen E, von Bergh AR, van den Heuvel-Eibrink MM, et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 2006;45:437–46. [12] Panagopoulos I, Kerndrup G, Carlsen N, Strombeck B, Isaksson M, Johansson B. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Br J Haematol 2007;136:294–6.

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Thioredoxin and hematologic malignancies.

Control of nucleocytoplasmic transport.

Immune markers in hematologic malignancies.

Epigenetics in the hematologic malignancies.

Arterial stiffness in hematologic malignancies.

Leptin and its receptor in hematologic malignancies.

Functional insights of nucleocytoplasmic transport in plants.

FTD.

Targeting nucleocytoplasmic transport in cancer therapy.

Expanding role of lenalidomide in hematologic malignancies.

Secondary pulmonary alveolar proteinosis in hematologic malignancies.

Role of molecular charge in nucleocytoplasmic transport.

Targeting cell cycle regulators in hematologic malignancies.

Targeting the apoptosis pathway in hematologic malignancies.

Carbapenemase-producing Klebsiella pneumoniae and hematologic malignancies.

Current Role of Genetics in Hematologic Malignancies.

Toxoplasmosis in patients with hematologic malignancies.

Acute tumor lysis syndrome in hematologic malignancies.

ABO blood groups in hematologic malignancies.

The treatment of hematologic malignancies in pregnancy.

Immune checkpoint blockade in hematologic malignancies.

Endothelial progenitor cells in hematologic malignancies.

The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.

Time-resolved biophysical approaches to nucleocytoplasmic transport.