The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK.

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.

Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases.

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

[MALT lymphoma with t (X;14) (p11.2;q32) developing during the course of cutaneous leukocytoclastic angitis].

A 73-year-old man with left parotid gland swelling over 2 months was referred to our hospital in March 201X. Purpura on the lower legs had been recurrent for >20 years. Biopsy of the parotid gland demonstrated diffuse infiltration of abnormal lymphocytes that were negative for CD10 and positive for CD19, CD20, and κ-chain. The Ki-67 positivity was <10%; lymphoepithelial lesions were observed. The patient was diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Chromosome analysis revealed t (X;14) (p11.2;q32), and fluorescence in situ hybridization (FISH) of metaphase spreads showed three signals of the immunoglobulin heavy chain (IGH) gene on the derivative chromosomes X and 14, besides the normal chromosome 14. CT findings of parotid glands were suggestive of Sjogren syndrome, and biopsy of the purpura on the leg demonstrated leukocytoclastic vasculitis. In the literature, only seven patients with lymphoma and t (X;14) translocation have been reported. Of these, five patients had MALT lymphoma, one had nodal marginal zone lymphoma, and one had diffuse large B-cell lymphoma. In all patients, lymphoma evolved from previous autoimmune diseases. It is suggested that MALT lymphoma with the t (X;14) translocation forms a new entity of lymphoma.

Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.

Acute myeloid leukemia with t(3;21)(q13;q22), a novel simple variant of the 21q22/RUNX1 translocation.

A 69-year-old man diagnosed with leukocytosis was referred to our hospital in July 201X. The patient was diagnosed as having a myelodysplastic/myeloproliferative neoplasm. However, he presented with leukemia 2 months later. Chromosomal analysis of a bone marrow sample documented that this patient had a normal karyotype. The patient was successfully treated with idarubicin and cytarabine, and he underwent three courses of consolidation therapy. However, he suffered a relapse in May of the following year. A cytogenetic analysis revealed the presence of a t (3;21) (q13;q22) translocation, and fluorescence in situ hybridization of metaphase spreads detected three signals corresponding to the runt related transcription factor 1 (RUNX1) on the derivative chromosomes 3 and 21, besides the normal chromosome 21. Chromosomal translocations in leukemia often involve genes encoding transcription factors, and the RUNX1 is a common target for such translocations. To the best of our knowledge, this is a novel variant of the RUNX1 translocation. Identifying genes associated with translocations in leukemia contributes to novel insights into the mechanisms of disease progression and chemotherapy resistance and also facilitates the development of molecularly targeted therapies.

Acute myeloid leukemia with t (3;8) (q26.2;q24), a simple variant of 3q26.2/EVI1 translocation.

A 70-year-old man with pancytopenia was referred to our hospital. His bone marrow comprised 75.4% leukemic blast cells and increased micromegakaryocytes. The leukemic cells were positive for myeloperoxidase and expressed CD2, CD13, CD33, CD34, CD56, CD117, HLA-DR, and MYC. Chromosomal analysis revealed 45,XY,t (3;8) (q26.2;q24),-7[6]/46,XY[14]. Fluorescence in situ hybridization revealed the rearrangement of the ecotropic viral integration site 1 (EVI1) gene. Thus, the patient was diagnosed as having acute myeloid leukemia (AML) with maturation, according to the WHO classification; he achieved complete cytogenetic remission after two courses of combination chemotherapy using anthracyclines and cytarabine. The t (3;8) translocation is a rare simple variant of the 3q26.2/EVI1 translocation, which is an adverse prognostic factor of AML. Clarifying the clinical features of leukemia in patients with simple variant translocations facilitates the development of therapies.

Pathological background of subcortical hyperintensities on diffusion-weighted images in a case of neuronal intranuclear inclusion disease.

AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with eosinophilic intranuclear inclusion bodies. The variable symptoms of NIID increase the difficulty in an antemortem diagnosis. NIID shows leukoencephalopathy on brain magnetic resonance imaging MRI, but the significance of the radiological findings have not been clarified. METHODS: We examined an autopsied case of NIID with subcortical linear hyperintensities on diffusion weighted imaging (DWI) and leukoencephalopathy on fluid attenuation inversion recovery (FLAIR) imaging. Semiquantitative analysis was performed by merging coronal sections of DWI and identical hematoxylin-eosin (H & E) stained brain specimens. The severity of spongiotic changes, the common pathological findings of NIID, were quantified and compared with MRI lesions classified by DWI signals. RESULTS: The white matter showed diffuse myelin pallor, and multiple focal spongiotic changes were present in the subcortical white matter proximal to the U-fibers. Spongiotic changes were restricted in the lesions with subcortical linear DWI high signals. CONCLUSION: Subcortical DWI high signals in NIID strongly correlate with pathological spongiotic changes of NIID. Subcortical spongiotic changes may be a characteristic finding of NIID.
.

Chronological changes of 123I-MIBG myocardial scintigraphy and clinical features of Parkinson's disease.

OBJECTIVES: The aim of this study was to investigate chronological changes of (123)I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy and its relation to clinical features in patients with Parkinson's disease (PD), and to characterise patients with PD with normal or mildly low MIBG uptakes at their early stages. METHODS: The participants were 70 patients with PD who underwent (123)I-MIBG myocardial scintigraphy twice or more. A cluster analysis was performed using parameters calculated from heart to mediastinum (H/M) ratio and washout ratio (WR). RESULTS: At baseline, the mean early H/M ratio (H/M(E)), delayed H/M ratio (H/M(D)) and WR were 1.83, 1.69 and 41.7%, respectively. After a mean interval of 3.0 years, follow-up studies showed significantly declined H/M(E) (1.69, p<0.001), declined H/M(D) (1.47, p<0.001) and enhanced WR (43.8%, p=0.007). Our longitudinal observations revealed that there existed heterogeneous changes in MIBG uptakes among patients. The cluster analysis classified the patients into two subgroups: 42 patients with markedly low MIBG uptakes at baseline (group A) and 28 patients with normal or mildly low MIBG uptakes at baseline (group B). Group B showed a significantly higher ratio of females, younger age at onset, lower Hoehn and Yahr stage and less demented, compared with group A. CONCLUSIONS: Follow-up studies of MIBG divided the patients with PD into two major subgroups. A subgroup of patients with PD with normal or mildly low MIBG uptakes at the early stages of illness was characterised by female-dominant, young onset, slow progression in motor dysfunctions and preserved cognitive function. TRIAL REGISTRATION NUMBER: 1033.

Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure.

BACKGROUND: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown. OBJECTIVE: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs). METHODS: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM. RESULTS: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort. CONCLUSIONS: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.

[A case of metachronal testicular tumor eight years after medical treatment of extragonadal germ cell tumor].

A 22-year-old man was admitted to our hospital complaining of a left cervical mass. Computed tomography (CT) showed multiple enlarged lymph nodes at the left cervical vein and para-aortic areas. Histological examination of a biopsy indicated an embryonal carcinoma. The levels of human ß-chorionic gonadotropin (ß-HCG) and lactic dehydrogenase (LDH) were both elevated. Ultrasonography revealed testicular calcification, but there were no findings on magnetic resonance imaging (MRI). The patient was diagnosed as having an extragonadal germ cell tumor. After four courses of chemotherapy with BEP protocol (bleomycin, etoposide and cisplatin), retroperineal lymph node dissection (RPLND) was performed and there was no involvement of the viable cells in the resected lymph nodes. Eight years after chemotherapy, he noticed an enlargement of his left scrotum without pain. ß-HCG was again elevated. A unilateral high orchiectomy was performed, and histology revealed a seminoma. He was staged as pT1N0M0S0. Six months later he remains disease-free.

IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.

Cytoplasmic aggregation of TDP-43 in neurons is a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We demonstrate that the IκB kinase (IKK) complex promotes the degradation of cytoplasmic TDP-43 through proteasomes. While IKKß is a major factor in TDP-43 degradation, IKKα acts as a cofactor, and NEMO functions as a scaffold for the recruitment of TDP-43 to the IKK complex. Furthermore, we identified IKKß-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. TDP-43 phosphorylation at Ser92 was detected in a pattern different from that of C-terminal phosphorylation in the pathological inclusion of ALS. IKKß was also found to significantly reduce the expression level and toxicity of the disease-causing TDP-43 mutation. Finally, the favorable effect of IKKß on TDP-43 aggregation was confirmed in the hippocampus of mice. IKK and the N-terminal phosphorylation of TDP-43 are potential therapeutic targets for ALS and FTLD.

Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies.

BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

Ubiquitin-related proteins in neuronal and glial intranuclear inclusions in intranuclear inclusion body disease.

Recent studies have shown that eosinophilic intranuclear inclusions (INI) in the brain of patients with intranuclear inclusion body disease (INIBD) are immunopositive for ubiquitin and ubiquitin-related proteins (URP). However, the extent and frequency of URP-immunoreactive inclusions in INIBD are uncertain. We immunohistochemically examined the brain, spinal cord and dorsal root ganglia from five patients with INIBD, using a virtual slide system with sequential staining of the same sections with hematoxylin and eosin and by immunolabeling with antibodies against ubiquitin and URP (NEDD8, NUB1, SUMO-1 and SUMO-2). Intranuclear inclusions were widely distributed in neurons and glial cells in all the cases. Sequential staining revealed that 100% of INI in neurons and glial cells were positive for ubiquitin. Moreover, the majority or a significant proportion of INI were positive for NEDD8, NUB1, SUMO-1 and SUMO-2. However, the proportions of NEDD8-, NUB1- and SUMO-1-positive inclusions were significantly higher in neurons than in glial cells (P < 0.05). These findings suggest that proteins related to ubiquitination and proteasomal degradation are involved in the formation of INI in INIBD.

A case of sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: long-term observation of neurological symptoms after autologous stem-cell transplantation.

A 47-year-old woman presented with progressive limb weakness. A neurological examination revealed proximal dominant symmetrical muscle weakness in her limbs, and electromyography revealed complex repetitive discharges and short motor unit potentials with positive sharp waves in the biceps. We observed early recruitment in the quadriceps, and laboratory tests revealed normal creatine kinase. Serum protein electrophoresis showed monoclonal IgG-lambda, but the bone marrow aspiration specimen was normal. A muscle biopsy revealed nemaline rod accumulations in the muscle fibers; based on the results, we diagnosed the patient with sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS). We administered repeated intravenous immunoglobulin, but her limb weakness continued, and she developed a restrictive ventilatory defect. The patient received melphalan, followed by autologous stem-cell transplantation (ASCT). Her upper extremity strength and respiratory capability improved within one year after ASCT; however, it was not until six years after ASCT that her atrophied lower extremities strengthened. A discrepancy in the timeline of treatment response between the upper or respiratory muscles and the atrophied lower limb was characteristic in the patient, suggesting that the efficacy of ASCT on SLONM-MGUS should be evaluated in the long term, especially in severely atrophied muscles. In addition, this case showed that ASCT for SLOMN-MGUS is an effective treatment option in Asian populations.

Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.

Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. In this study, we applied a novel detection method using a conventional antigen retrieval technique with Sudan Black B treatment to identify FUS-positive inclusions in sALS patients. We classified pathological motor neurons into 5 different categories according to the different aggregation characteristics of FUS and TDP-43. Although the granular type was more dominant for inclusions with TDP-43, the skein-like type was more often observed in FUS-positive inclusions, suggesting that these 2 proteins undergo independent aggregation processes. Moreover, neurons harboring FUS-positive inclusions demonstrated substantially reduced expression levels of dynactin-1, a retrograde motor protein, indicating that perturbation of nucleocytoplasmic transport is associated with the formation of cytoplasmic inclusions of FUS in sALS.

Evaluation of docetaxel plus estramustine in the treatment of patients with hormone-refractory prostate cancer.

OBJECTIVES: To investigate the feasibility and efficacy of docetaxel-based chemotherapy in patients with hormone-refractory prostate cancer (HRPC). METHODS: Forty-six consecutive HRPC patients treated between January 2003 and March 2008 were included in this analysis. Docetaxel was given at a dose of 35 mg/m(2) twice every 3 weeks and oral estramustine concurrently for three consecutive days during weeks 1 and 2 of each cycle. During each treatment week, the dose of estramustine was 1260 mg on the first day, 980 mg on the second day and 840 mg on the third day. Patients were premedicated with 4 mg twice a day of oral dexamethasone for three consecutive days. Treatment was continued until evidence of disease progression or unacceptable toxicity. Prostate-specific antigen (PSA) levels were evaluated at least once every 4 weeks. RESULTS: Patients received a median of three cycles of chemotherapy. Of the evaluable 46 patients, 25 (54%) had a >or=50% PSA decline and 12 (26%) had a >or=75% PSA decline. Median time to PSA progression and overall survival time were 10.1 and 27.0 months, respectively. Median follow-up was 15.0 months. Major severe toxicities were grade 3 or 4 leukopenia in five (11%) patients. Mild toxicities included grade 1 or 2 nausea in eight (17%) patients. Two patients could not continue the treatment because of interstitial pneumonitis and a gastric hemorrhage, respectively. CONCLUSIONS: Docetaxel plus estramustine chemotherapy represents an active and well tolerated treatment for Japanese HRPC patients.

Correction to: Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

In the original publication of the article, Table 2 was published incorrectly. The column names were swapped under the column heading "Prom (%)". The correct column names are PB and BM.

Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

3'UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function.

FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS's regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion. Moreover, FUS and the ELAV-like proteins ELAVL4 and ELAVL1 control SynGAP mRNA stability in a 3'UTR length-dependent manner, resulting in the stable expression of the alternatively spliced SynGAP isoform α2. Finally, abnormal spine maturation and FTLD-like behavioral deficits in FUS-knockout mice were ameliorated by SynGAP α2. Our findings establish an important link between FUS and ELAVL proteins for mRNA stability control and indicate that this mechanism is crucial for the maintenance of synaptic morphology and cognitive function.