Molecular mechanisms driving the interactions between platelet and gastric cancer cells during peritoneal dissemination.

Platelets (PLTs) facilitate tumor progression and the spread of metastasis. They also interact with cancer cells in various cancer types. Furthermore, PLTs form complexes with gastric cancer (GC) cells via direct contact and promote their malignant behaviors. The objective of the present study was to explore the molecular mechanisms driving these interactions and to evaluate the potential for preventing peritoneal dissemination by inhibiting PLT activation in GC cells. The present study examined the roles of PLT activation pathways in the increased malignancy of GC cells facilitated by PLT-cancer cells. Transforming growth factor-ß receptor kinase inhibitor (TRKI), Src family kinase inhibitor (PP2) and Syk inhibitor (R406) were used to identify the molecules influencing these interactions. Their therapeutic effects were verified via cell experiments and validated using a mouse GC peritoneal dissemination model. Notably, only the PLT activation pathway-related inhibitors TRKI and PP2, but not R406, inhibited the PLT-enhanced migration and invasion of GC cells. In vivo analyses revealed that PLT-enhanced peritoneal dissemination was suppressed by PP2. Overall, the present study revealed the important role of the Srk family in the interactions between PLTs and GC cells, suggesting kinase inhibitors as promising therapeutic agents to mitigate the progression of peritoneal metastasis in patients with GC.

Changes in and clinical utility of maximum phonation time and repetitive saliva swallowing test scores after esophagectomy.

BACKGROUND: Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy. METHODS: In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia. RESULTS: The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis. CONCLUSIONS: The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia.

Differences in glycemic trends due to reconstruction methods after proximal gastrectomy from the perspective of continuous glucose-monitoring.

PURPOSE: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer. METHODS: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks. RESULTS: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively). CONCLUSION: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer.

Re-consideration of Lymph Node Metastasis in Pancreatic Cancer Patients Following Radical Resection: A Retrospective Study.

BACKGROUND/AIM: Perioperative chemotherapy has become more common in patients with pancreatic cancer (PC), and the significance of lymph node (LN) metastasis and the role of surgical resection in PC have gradually evolved. In the present study, we reconsidered the significance of LN metastasis for patients with PC. PATIENTS AND METHODS: We analyzed 142 PC patients who underwent radical resection at our hospital between September 2012 and December 2021. Patients were divided into three groups based on the performance of preoperative chemotherapy, as follows: up-front surgery (US, n=109), neoadjuvant chemotherapy (NAC, n=22), and conversion surgery (CS, n=11). The characteristics of patients with LN metastasis in the US group were clarified, and a prognostic analysis was performed. The prognostic impact of LN metastasis in the NAC/CS group was examined and compared to that in the US group. RESULTS: Multivariate analysis revealed that high CA19-9 levels, large tumor size, and positive lymphatic invasion were significantly associated with LN metastasis. LN metastasis and portal vein invasion were independent poor prognostic factors in multivariate analysis. Patients without LN metastasis in the NAC group tended to have a better prognosis than those in the US group; however, the prognosis of patients with LN metastasis was similar between the two groups. In the CS and US groups, the prognosis was comparable for patients with and without LN metastasis. CONCLUSION: LN metastasis is a notably poor prognostic factor for PC patients, even after NAC, and more aggressive perioperative treatments may be considered for these patients.

Investigating Cytoglobin Expression in Colon Cancer: Clinicopathological Insights from Immunohistochemical Analysis.

BACKGROUND/AIM: Cytoglobin (Cygb), a protein involved in cellular oxygen metabolism and protection, has garnered attention owing to its potential role in the initiation and progression of cancer, particularly colon cancer (CC). This study investigated the expression and significance of Cygb in CC. PATIENTS AND METHODS: This study included 145 patients who underwent R0 surgery for CC (clinical stage II/III) at our institution between January 2007 and December 2014. Immunohistochemical analysis was performed to evaluate the Cygb expression patterns in CC tissues. Additionally, the correlation between Cygb expression levels and the clinicopathological characteristics of patients with CC was investigated. RESULTS: Colon cancer tissues were categorized into high-expression (95 cases) and low-expression (50 cases) groups. Cygb was highly expressed in well-differentiated cases, whereas its expression decreased in poorly differentiated cases. No significant differences in other clinicopathological factors were observed between the two groups. Cygb expression had no significant effect on recurrence-free survival or overall survival. CONCLUSION: This study contributes to the growing understanding of Cygb expression and its significance in CC. The expression of Cygb in CC was found to be unrelated to the recurrence rate and prognosis, but showed a correlation with differentiation status.

Prognostic Impact of Stromal Profiles Educated by Gastric Cancer.

BACKGROUND: Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. METHODS: Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. RESULTS: Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. CONCLUSIONS: Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Analysis of surgical outcomes and risk factors for anastomotic leakage following trans-hiatal resection of esophagogastric junction cancer.

BACKGROUND: The trans-hiatal lower esophagectomy is considered less invasive than the trans-thoracic esophagectomy for resection of esophagogastric junction (EGJ) cancer. However, the optimal procedure remains controversial and should be determined while considering both oncological and safety aspects. METHODS: This retrospective study comprised 124 patients that underwent curative resection for EGJ cancer. The study analysis included 93 patients with tumor centers located within 2 cm of the EGJ. Clinicopathological findings and surgical outcomes were compared between patients treated using trans-hiatal and trans-thoracic approaches. RESULTS: Sixty-three patients underwent lower esophagectomy using the trans-hiatal approach (TH-G). The remaining 30 patients underwent esophagectomy using the trans-thoracic approach (TT-E). The TH-G group were older, had a lower prevalence of lymphatic spread, shorter length of esophageal invasion, and shorter operative duration compared to the TT-E group. Although no significant differences in the frequency of postoperative complications, a higher proportion of patients in the TH-G group developed anastomotic leakage (16% vs. 7%, p = 0.33). Univariate and multivariate analyses demonstrated that cardiac comorbidity was an independent risk factor for anastomotic leakage (odds ratio, 5.24; 95% CI, 1.06-25.9; P < 0.05) in TH-G group. Further examination revealed that preoperative cardiothoracic ratio (CTR) with 50% or greater could be surrogate marker as risk factor for anastomotic leakage in TH-G group (35% vs. 7.5%, p < 0.05). CONCLUSIONS: The trans-hiatal approach can be used for resection of EGJ cancer. However, special attention should be paid to the prevention of anastomotic leakage in patients with cardiac comorbidities or a large preoperative CTR.

Successful selective production of vanillic acid from depolymerized sulfite lignin and its application to poly(ethylene vanillate) synthesis.

Towards lignin upgrading, vanillic acid (VA), a lignin-derived guaiacyl compound, was produced from sulfite lignin for successfully synthesizing poly(ethylene vanillate), an aromatic polymer. The engineered Sphingobium sp. SYK-6-based strain in which the genes responsible for VA/3-O-methyl gallic acid O-demethylase and syringic acid O-demethylase were disrupted was able to produce vanillic acid (VA) from the mixture consisting of acetovanillone, vanillin, VA, and other low-molecular-weight aromatics obtained by Cu(OH)2-catalyzed alkaline depolymerization of sulfite lignin and membrane fractionation. From the bio-based VA, methyl-4-(2-hydroxyethoxy)-3-methoxybenzoate was synthesized via methylesterification, hydroxyethylation, and distillation, and then it was subjected to polymerization catalyzed by titanium tetraisopropoxide. The molecular weight of the obtained poly(ethylene vanillate) was evaluated to be Mw = 13,000 (Mw/Mn = 1.99) and its melting point was 261 °C. The present work proved that poly(ethylene vanillate) is able to be synthesized using VA produced from lignin for the first time.

Cystic degeneration during neo-adjuvant chemotherapy predicts squamous metaplasia of triple negative breast cancer: report of two cases.

Neo-adjuvant chemotherapy (NAC) has become a standard treatment for advanced breast cancer because of the advantage of monitoring drug sensitivity and enabling breast-conserving therapy. The changes during NAC are also important to know the biological characteristics of the tumor. We experienced two cases with cystic degeneration and enhancement of the cyst wall during NAC for triple negative breast cancer (TNBC). They were diagnosed to have breast cancer with squamous metaplasia. In case 1, a 37-year-old woman with right breast cancer diagnosed as TNBC, T3N3M0, Stage 3b was treated with NAC. MRI showed a cystic degeneration with a diameter of 3.5 cm and enhancement of the cyst wall, and the other nodules were extinguished. The histopathological finding of the surgical specimen revealed solid tubular carcinoma with squamous metaplasia. In case 2, a 58-year-old woman with right breast cancer diagnosed as HER2 enriched subtype, T2N0M0 stage 2 was treated with NAC containing trastuzumab. The post-NAC MRI showed extinguishment of the mass in the right breast, but showed a cystic lesion with 24 mm in diameter and enhancement of its wall in the left breast. She underwent breast conserving surgery for bilateral breast cancer, and histopathological finding of the surgical specimen indicated complete remission of right breast cancer and squamous cell carcinoma developed in the left breast. These changes are impressive and remind us that there are metaplastic changes (especially for squamous metaplasia) with resistance to chemotherapy.

Benefit of home parenteral nutrition (HPN) and chemotherapy in patients with invasive lobular carcinoma developed peritoneal metastases.

The benefit of home parenteral nutrition (HPN) for patients with malnutrition due to peritoneal metastasis depends on the type of cancer. During the period 1999-2020, we treated 460 patients with metastatic and stage 4 breast cancer, 23 of whom were invasive lobular carcinoma (ILC). Of the 23 patients with ILC, 13 (57%) developed peritoneal metastasis, and 11 died of progression of peritoneal metastasis. Among these 11 patients, 2 patients who underwent surgery due to bowel obstruction, had no improvement, and died 1-4 months after surgery. The prognosis of the other 7 patients under BSC alone was poor, survival time were ranging from 1 to 5 months. The remaining two patients who were able to continue outpatient chemotherapy under HPN were able to prolong their survival time by 18 months and 26 months, respectively. We need to recognize that HPN and chemotherapy may prolong survival time in patients with peritoneal metastasis of ILC, and determine the indication for HPN based on the non-peritoneal life-threatening metastasis, length of treatment, availability of support for HPN management and outpatient chemotherapy, and the patient's willingness to accept it.

Stroke Volume Variation Monitoring to Minimize Blood Loss in Hepatocellular Carcinoma Resection.

BACKGROUND/AIM: We aimed to evaluate the correlation between stroke volume variation (SVV) and intraoperative blood loss (IBL) in hepatocellular carcinoma (HCC) resection and examine the perioperative utility of SVV-based management. PATIENTS AND METHODS: Ninety-five patients who underwent partial or sub-segmental hepatectomy for HCC between 2013 and 2019 at the University of Yamanashi Hospital were retrospectively analyzed. A correlation analysis between IBL and SVV was performed, and then all cases were divided into three groups: high, middle, and low-SVV groups. Perioperative short-term outcomes based on SVV groups were analyzed. RESULTS: There was a weak but significant negative correlation between SVV and IBL (ρ=-0.372, p<0.001). Comparative analysis revealed that low-SVV was associated with a high incidence of postoperative complications and blood transfusion (p=0.018 and 0.037, respectively), and high-SVV was not related with postoperative complications. CONCLUSION: SVV-based management is a significant and feasible strategy to achieve safe and exact surgical resection of HCC.

Early Drain Removal Regardless of Drain Fluid Amylase Level Might Reduce Risk of Postoperative Pancreatic Fistula.

BACKGROUND/AIM: Drains are frequently placed at the time of distal pancreatectomy (DP) to evacuate pancreatic juice and intra-abdominal exudate and obtain information on abdominal cavity status. However, the timing of drain removal remains debatable. Meanwhile, prolonged drain placement might increase the risk of postoperative pancreatic fistula (POPF), with a prevalence of 5-40%. Therefore, we examined the effect of removing the drain within postoperative day (POD) 3 on the risk of POPF development. PATIENTS AND METHODS: A total of 108 consecutive patients who underwent DP between April 2015 and March 2020 were examined and divided into two groups according to the day of drain removal; hence, for some patients, the drain was removed on POD 1 (POD 1 group) and for others on POD 3 (POD 3 group). Furthermore, risk factors, including drain fluid amylase (DFA) levels, for developing POPF were investigated. RESULTS: The overall rate of clinically relevant POPF was 4.6% and did not significantly differ between the POD 1 and POD 3 groups [4.5% and 4.9%, respectively (p=0.924)]. DFA levels on POD 1 did not significantly differ between patients with and without POPF. On POD 3 and POD 5, C-reactive protein (CRP) levels were significantly higher in patients with POPF than in those without (p=0.03 and p<0.001, respectively). CONCLUSION: Early drain removal regardless of DFA level may reduce the risk of developing POPF. CRP measured on POD 3 and POD 5 appeared to be a useful predictor of clinically relevant POPF.

[Nab-Paclitaxel plus Gemcitabine for Patients with Recurrence after Resection for Adenocarcinoma of the Pancreas].

PURPOSE: The purpose of this study was to clarify the predictors of efficacy of nab-paclitaxel plus gemcitabine(GnP)for patients with recurrence after resection for adenocarcinoma of the pancreas. METHOD: Patients who had received GnP at our hospital were divided into 2 groups; effective group and non-effective group and we compared them. In addition, we compared the therapeutic effect of patients between well-differentiated adenocarcinoma and moderately differentiated adenocarcinoma. Furthermore, we compared the efficacy depending on the time of recurrence. RESULTS: In patients with well-differentiated adenocarcinoma, the disease control rate was 93.6% and progression free survival was 8.6 months, whereas those in patients with moderately differentiated adenocarcinoma were 57.1% and 4.4 months, respectively. Patients who recurred at 7 months or later, had a better therapeutic response than the patients who recurred within 6 months after surgery. CONCLUSIONS: GnP may be effective in patients with well-differentiated adenocarcinoma and in patients who recurred at 7 months or later.

Roles of two glutathione S-transferases in the final step of the ß-aryl ether cleavage pathway in Sphingobium sp. strain SYK-6.

Sphingobium sp. strain SYK-6 is an alphaproteobacterial degrader of lignin-derived aromatic compounds, which can degrade all the stereoisomers of ß-aryl ether-type compounds. SYK-6 cells convert four stereoisomers of guaiacylglycerol-ß-guaiacyl ether (GGE) into two enantiomers of α-(2-methoxyphenoxy)-ß-hydroxypropiovanillone (MPHPV) through GGE α-carbon atom oxidation by stereoselective Cα-dehydrogenases encoded by ligD, ligL, and ligN. The ether linkages of the resulting MPHPV enantiomers are cleaved by stereoselective glutathione (GSH) S-transferases (GSTs) encoded by ligF, ligE, and ligP, generating (ßR/ßS)-α-glutathionyl-ß-hydroxypropiovanillone (GS-HPV) and guaiacol. To date, it has been shown that the gene products of ligG and SLG_04120 (ligQ), both encoding GST, catalyze GSH removal from (ßR/ßS)-GS-HPV, forming achiral ß-hydroxypropiovanillone. In this study, we verified the enzyme properties of LigG and LigQ and elucidated their roles in ß-aryl ether catabolism. Purified LigG showed an approximately 300-fold higher specific activity for (ßR)-GS-HPV than that for (ßS)-GS-HPV, whereas purified LigQ showed an approximately six-fold higher specific activity for (ßS)-GS-HPV than that for (ßR)-GS-HPV. Analyses of mutants of ligG, ligQ, and both genes revealed that SYK-6 converted (ßR)-GS-HPV using both LigG and LigQ, whereas only LigQ was involved in converting (ßS)-GS-HPV. Furthermore, the disruption of both ligG and ligQ was observed to lead to the loss of the capability of SYK-6 to convert MPHPV. This suggests that GSH removal from GS-HPV catalyzed by LigG and LigQ, is essential for cellular GSH recycling during ß-aryl ether catabolism.

Discovery of novel enzyme genes involved in the conversion of an arylglycerol-ß-aryl ether metabolite and their use in generating a metabolic pathway for lignin valorization.

Microbial conversions known as "biological funneling" have attracted attention for their ability to upgrade heterogeneous mixtures of low-molecular-weight aromatic compounds obtained by chemical lignin depolymerization. ß-hydroxypropiovanillone (HPV) and its analogs can be obtained by chemoselective catalytic oxidation of lignin using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone/tert-butyl nitrite/O2, followed by cleavage of arylglycerol-ß-aryl ether with zinc. Sphingobium sp. strain SYK-6 can degrade HPV generated by the catabolism of arylglycerol-ß-aryl ether through 2-pyrone-4,6-dicarboxylate (PDC), a promising platform chemical. Therefore, production of PDC from HPV can be achieved using the HPV catabolic pathway. However, the pathway and genes involved in the catabolism of vanilloyl acetic acid (VAA) generated during HPV catabolism have not been investigated. In the present study, we isolated SLG_24960 (vceA), which encodes an enzyme that converts VAA into a coenzyme A (CoA) derivative of vanillate (vanilloyl-CoA) from SYK-6, by shotgun cloning. The analysis of a vceA mutant indicated that this gene is not required for VAA conversion in vivo, but it encodes a major enzyme catalyzing CoA-dependent VAA conversion in vitro. We also identified SLG_12450 (vceB), whose product can convert vanilloyl-CoA to vanillate. Enzyme genes besides vceA and vceB, which are necessary for the conversions of HPV to VAA and of vanillate to PDC, were introduced and expressed in Pseudomonas putida. The resulting engineered strain completely converted 1  mM HPV into PDC after 24  h. Our results suggest that the enzyme genes that are not required for the catabolic pathway in microorganisms but can be used for the conversion of target substrates are buried in microbial genomes. These genes are, thus, useful for designing metabolic pathways to produce value-added metabolites.

Bacterial Catabolism of ß-Hydroxypropiovanillone and ß-Hydroxypropiosyringone Produced in the Reductive Cleavage of Arylglycerol-ß-Aryl Ether in Lignin.

Sphingobium sp. strain SYK-6 converts four stereoisomers of arylglycerol-ß-guaiacyl ether into achiral ß-hydroxypropiovanillone (HPV) via three stereospecific reaction steps. Here, we determined the HPV catabolic pathway and characterized the HPV catabolic genes involved in the first two steps of the pathway. In SYK-6 cells, HPV was oxidized to vanilloyl acetic acid (VAA) via vanilloyl acetaldehyde (VAL). The resulting VAA was further converted into vanillate through the activation of VAA by coenzyme A. A syringyl-type HPV analog, ß-hydroxypropiosyringone (HPS), was also catabolized via the same pathway. SLG_12830 (hpvZ), which belongs to the glucose-methanol-choline oxidoreductase family, was isolated as the HPV-converting enzyme gene. An hpvZ mutant completely lost the ability to convert HPV and HPS, indicating that hpvZ is essential for the conversion of both the substrates. HpvZ produced in Escherichia coli oxidized both HPV and HPS and other 3-phenyl-1-propanol derivatives. HpvZ localized to both the cytoplasm and membrane of SYK-6 and used ubiquinone derivatives as electron acceptors. Thirteen gene products of the 23 aldehyde dehydrogenase (ALDH) genes in SYK-6 were able to oxidize VAL into VAA. Mutant analyses suggested that multiple ALDH genes, including SLG_20400, contribute to the conversion of VAL. We examined whether the genes encoding feruloyl-CoA synthetase (ferA) and feruloyl-CoA hydratase/lyase (ferB and ferB2) are involved in the conversion of VAA. Only FerA exhibited activity toward VAA; however, disruption of ferA did not affect VAA conversion. These results indicate that another enzyme system is involved in VAA conversion.IMPORTANCE Cleavage of the ß-aryl ether linkage is the most essential process in lignin biodegradation. Although the bacterial ß-aryl ether cleavage pathway and catabolic genes have been well documented, there have been no reports regarding the catabolism of HPV or HPS, the products of cleavage of ß-aryl ether compounds. HPV and HPS have also been found to be obtained from lignin by chemoselective catalytic oxidation by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone/tert-butyl nitrite/O2, followed by cleavage of the ß-aryl ether with zinc. Therefore, value-added chemicals are expected to be produced from these compounds. In this study, we determined the SYK-6 catabolic pathways for HPV and HPS and identified the catabolic genes involved in the first two steps of the pathways. Since SYK-6 catabolizes HPV through 2-pyrone-4,6-dicarboxylate, which is a building block for functional polymers, characterization of HPV catabolism is important not only for understanding the bacterial lignin catabolic system but also for lignin utilization.

Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia.

The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML.