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[Abstract] Background: Thrombopoietin (TPO) and its receptor, c-Mpl are essential for megakaryopoiesis. Two TPO receptor agonists (TPO-RAs),Eltrombopag (ETP) and Romiplostim (Rom), which also activate c-Mpl, thereby transmitting signals to downstream molecules, are currently used for immune thrombocytopenia purpura and aplastic anemia. Furthermore, recent clinical trials demonstrated that ETP and Rom would be useful for Myelodysplastic syndromes (MDS) patients with thrombocytopenia. Lusutrombopag (LTP) is a novel TPO-RA, which is approved for thrombocytopenia associated with liver diseases. In this study, we examined the effects of LTP on the growth and differentiation of MDS CD34+ cells as a preclinical study. Method: Effects of LTP on the proliferation, differentiation, and long-term self-renewal activities of bone marrow CD34+ cells from MDS patients were assessed with liquid cultures, CFU-megakaryocyte assays, and serial replating assays, respectively. We also analyzed the effects of LTP on cytokine secretion from cultured MDS CD34+ cells with a cytokine antibody array. Results: LTP effectively promotes the growth and differentiation of MDS CD34+ cells with comparable efficacy to that exerted on CD34+ cells from healthy controls. The megakaryopoietic potential of LTP was comparable to that exerted by ETP and TPO. LTP did not stimulate growth of CD34+ MDS/AML blasts, a concern that has been associated with ETP and Rom. Both ETP and TPO induced higher levels of FGF7 than LTP from CD34+ MDS cells. Conclusion: Although LTP and ETP revealed some different biologic activities, LTP would be as effective as ETP in promoting the growth and megakaryocytic differentiation of MDS CD34+ cells.

We previously reported that the antipsychotic drug chlorpromazine (CPZ), which inhibits the formation of clathrin-coated vesicles (CCVs) essential for endocytosis and intracellular transport of receptor tyrosine kinase (RTK), inhibits the growth/survival of acute myeloid leukemia cells with mutated RTK (KIT D816V or FLT3-ITD) by perturbing the intracellular localization of these molecules. Here, we examined whether these findings are applicable to epidermal growth factor receptor (EGFR). CPZ dose-dependently inhibited the growth/survival of the non-small cell lung cancer (NSCLC) cell line, PC9 harboring an EGFR-activating (EGFR exon 19 deletion). In addition, CPZ not only suppressed the growth/survival of gefitinib (GEF)-resistant PC9ZD cells harboring T790 M, but also restored their sensitivities to GEF. Furthermore, CPZ overcame GEF resistance caused by Met amplification in HCC827GR cells. As for the mechanism of CPZ-induced growth suppression, we found that although CPZ hardly influenced the phosphorylation of EGFR, it effectively reduced the phosphorylation of ERK and AKT. When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. Immunofluorescent staining revealed that EGFR shows a perinuclear pattern and was intensely colocalized with the late endosome marker, Rab11. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is an important public health issue worldwide, not only due to the potential of these pathogens for widespread dissemination, but also due to the limited antimicrobial therapy options, and the elevated mortality rates associated with these infections. As with other multidrug-resistant organisms (MDROs), active surveillance via timely testing, early diagnosis, and contact isolation is an important strategy to control the occurrence and spread of CRE bacteria. Here we summarize the epidemiology of CRE infections in Japan from 2015 to 2019. Data were extracted from a public dataset collected by the nationwide surveillance system via the National Institute of Infectious Diseases (NIID) of Japan. The annual number of reported CRE infections has remained relatively stable, with a tendency to increase in the last two years (1671 cases reported in 2015 and 2333 cases reported in 2019). The majority of patients who presented CRE infections over this five year period were older than 65 years (~80%, mean age 75), 60% of them were men, and mortality rates were around 3.5%. Importantly, about 60% of infections are caused by both

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Carbapenem-resistant Enterobacteriaceae (CRE) are gram-negative bacteria that are resistant to carbapenems, a group of antibiotics considered as the last-resource for the treatment of infections caused by multidrug-resistant bacteria. CRE constitutes a major threat to health care systems because infections caused by these pathogens are difficult to treat and are commonly associated with high mortality due to the limited availability of effective antibiotics. While infection prevention and timely detection are of vital importance to control CRE infections, developing new and effective anti-CRE therapies is also crucial. Accumulating evidence indicates that gut microbiota alteration (dysbiosis) is associated with an increased intestinal colonization with CRE and consequently with higher risk of developing CRE infections. Importantly, therapeutic interventions aimed to modify the gut microbiota composition via fecal microbiota transplantation (FMT) have been explored in various clinical settings with some of them showing promising results, although larger clinical trials are needed to confirm the efficacy of this strategy. Here, we highlight the challenges associated with the emergence of CRE infections.

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to two-cycles of R-CHOP. The aim of this study was to identify molecular biomarkers that can predict prognosis in the RB-treated patients in the context of the prospective cohort. We first analyzed mutational status of 410 genes in diagnostic tumor specimens by target capture and sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however, none of which was predictive for progression-free survival (PFS) in the RB-treated patients (n=34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or immune response showed that expressions of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within 24 months (POD24)-group (n=8) than in noPOD24-group (n=31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS by using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n=19) and IISlow (n=20) groups. The 3-year PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], p=0.0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r=0.460, p=0.00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000013795, jRCT:051180181).

NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1β and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

Side population (SP) is known to include therapy-resistant cells in various cancers. Here, we analyzed SP using multiple myeloma (MM) samples. The SP accounted for 2.96% in MM cells from newly diagnosed MM (NDMM). CD34 was expressed in 47.8% of SP cells, but only in 2.11% of bulk MM cells. CD34

The prevalence of Carbapenem-resistant Enterobacteriaceae (CRE) has increased dramatically in recent years and has become a global public health issue. Since carbapenems are considered the last drugs of choice, infections caused by these pathogens are difficult to treat and carry a high risk of mortality. Several antibiotic combination regimens have been utilized for the management of CRE infections or to eradicate colonization in CRE carriers with variable clinical responses. In addition, recent studies have explored the use of fecal microbiota transplantation (FMT) to eradicate CRE infections. Here, we conducted a systematic review of publications in which FMT was used to eliminate CRE colonization in infected individuals. We searched the PubMed, Cochrane, and Medline databases up to November 30, 2021. Ten studies (209 patients) met the inclusion criteria for this review with three articles describing retrospective cohorts (n = 53 patients) and seven reporting prospective data (n = 156 patients), including one randomized open-label clinical trial. All studies were published between 2017 and 2021 with eight studies from Europe and two from South Korea. There were substantial variations in terms of outcome measurements and study endpoint among these studies. Among the 112 FMT recipients with confirmed CRE colonization, CRE decolonization was reported in 55/90 cases at one month after FMT and at the end of the study follow-up (6-12 months), decolonization was documented in 74/94 (78.7%) patients. The predominant CRE strains reported were Klebsiella pneumoniae and Escherichia coli and the most frequently documented carbapenemases were KPC, OXA-48, and NDM. In general, FMT was well tolerated, with no severe complications reported even in immunosuppressed patients and in those with multiple underlying conditions. In conclusion, FMT appears to be safe and effective in eradicating CRE colonization, however, more studies, especially randomized trials, are needed to validate the safety and clinical utility of FMT for CRE eradication.

Background: Several clinical risk stratification models have been proposed to predict the clinical outcomes of follicular lymphoma (FL) cases, however, few reports are available to predict prognosis of FL cases receiving bendamustine-based regimens. We previously examined the utility of rituximab-bendamustine (RB) treatment for newly diagnosed advanced FL, who showed non-optimal responses to two cycles of R-CHOP therapy. Methods: In this study, we explored the biomarkers that could influence outcomes for the RB-treated FL cases in the context of the prospective cohort by target capture and sanger sequencing, and gene-expression profiling analyses using 50 diagnostic biopsies.Results: We first examined the mutational status of 410 genes in tumor specimens derived from RB-treated cases. As reported before, CREBBP, KMT2D, MEF2B, BCL2, EZH2, CARD11, TNFRSF14, EP300, and APC were recurrently mutated, however, none of which was predictive for progression-free survival (PFS) in RB-treated cases. Similarly, the m7-FLIPI did not correlate with PFS or progression of disease within 24 months (POD24). A gene expression analysis using a panel of 770 genes associated with carcinogenesis and/or immune response showed that the expression of CD8+ T-cell markers (GZMM, FLT3LG, CD8A, CD8B, GZMK) and half of the genes regulating Th1 and Th2 responses were significantly lower in the POD24 group than in the noPOD24 group. Finally, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and dichotomized RB-treated cases into immune infiltrationhigh (infilhigh) and infiltrationlow (infillow) clusters. The 3-years PFS rate was lower in the infillow cluster than in the infilhigh cluster (50.0% [95% CI: 27.1–69.2%] vs. 84.2% [95% CI: 58.7–94.6%], p=0.0237). Of note, the proportion of cases with peripheral lymphopenia (low cluster than in the infilhigh cluster (38.5% vs. 9.09%, OR: 6.25 [95%CI, 1.20-32.7], p=0.0235). Conclusion: These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL cases.Trial registration: This trial was retrospectively registered in UMIN on April. 24, 2014 (UMIN000013795; http://www.umin.ac.jp/icdr/index-j.html).

Sarcoidosis is a rare inflammatory disease characterized by the development of granulomas in various organs, especially in the lungs and lymph nodes. Clinics of the disease largely depends on the organ involved and may range from mild symptoms to life threatening manifestations. Over the last two decades, significant advances in the diagnosis, clinical assessment and treatment of sarcoidosis have been achieved, however, the precise etiology of this disease remains unknown. Current evidence suggests that, in genetically predisposed individuals, an excessive immune response to unknown antigen/s is crucial for the development of sarcoidosis. Epidemiological and microbiological studies suggest that, at least in a fraction of patients, microbes or their products may trigger the immune response leading to sarcoid granuloma formation. In this article, we discuss the scientific evidence on the interaction of microbes with immune cells that may be implicated in the immunopathogenesis of sarcoidosis, and highlight recent studies exploring potential implications of human microbiota in the pathogenesis and the clinical course of sarcoidosis.

The plasticity of induced pluripotent stem cells (iPSCs) with the potential to differentiate into virtually any type of cells and the feasibility of generating hematopoietic stem progenitor cells (HSPCs) from patient-derived iPSCs (iPSC-HSPCs) has many potential applications in hematology. For example, iPSC-HSPCs are being used for leukemogenesis studies and their application in various cell replacement therapies is being evaluated. The use of iPSC-HSPCs can now provide an invaluable resource for the study of diseases associated with the destruction of HSPCs, such as bone marrow failure syndromes (BMFSs). Recent studies have shown that generating iPSC-HSPCs from patients with acquired aplastic anemia and other BMFSs is not only feasible, but is also a powerful tool for understanding the pathogenesis of these disorders. In this article, we highlight recent advances in the application of iPSCs for disease modeling of BMFSs and discuss the discoveries of these studies that provide new insights in the pathophysiology of these conditions.

Chronic kidney disease (CKD) constitutes a major health problem and one of the leading causes of death worldwide. Patients with CKD have impaired immune functions that predispose them to an increased risk of infections, as well as virus-associated cancers and a diminished vaccine response. In this study, we aimed to identify clinical and laboratory parameters associated with in-hospital mortality in patients evaluated in the department of emergency (ER) and admitted with the diagnosis of severe acute respiratory syndrome (SARS) caused by coronavirus disease 2019 (COVID-19) at the Baptist Hospital of Nicaragua (BHN). There were 37 patients with CKD, mean age 58.3 ± 14.1 years, admitted to BHN due to COVID-19, and among them, 24 (65.7%) were males (p = 0.016). During hospitalization, 23 patients with CKD (62.1%) died of complications associated with COVID-19 disease, which was a higher proportion (odds ratio (OR) 5.6, confidence interval (CI) 2.1–15.7, p = 0.001) compared to a group of 70 patients (64.8% males, mean age 57.5 ± 13.7 years) without CKD admitted during the same period in whom 28.5% died of COVID-19. In the entire cohort, the majority of patients presented with bilateral pneumonia, and the most common symptoms at admission were dyspnea, cough, and fever. Serum levels of D-dimer, ferritin and procalcitonin were significantly higher in patients with CKD compared with those without CKD. Multivariate analysis revealed that CKD, age (&gt, 60 years), and hypoxia measured in the ER were factors associated with increased in-hospital mortality. Among patients with CKD but not in those without CKD (OR 36.8, CI 1.5–88.3, p = 0.026), an increased monocytes-to-lymphocyte ratio (MLR) was associated with higher mortality and remained statistically significant after adjusting for confounders. The MLR measured in the ER may be useful for predicting in-hospital mortality in patients with CKD and COVID-19 and could contribute to early risk stratification in this group.

Acute myeloid leukemia (AML) is a heterogeneous disease often associated with poor prognosis. We previously showed that the localization of KIT-D816V at endolysosomes is critical to activate aberrant Akt signaling and Chlorpromazine (CPZ) perturbs the intracellular localization, leading to cell death in AML cells with KIT-D816V. We report that daily administration of CPZ, prescribed for controlling anxiety disorder in patient with AML harboring KIT-D816V, led to a dramatic reduction in AML cells. In vitro and in vivo experiments showed that CPZ inhibited the growth and survival of the patient-derived AML cells, implying potent efficacy of CPZ in AML with KIT-D816V.

Nearly one-quarter of all cancer deaths worldwide are due to lung cancer, making this disease the leading cause of cancer death among both men and women. The most important determinant of survival in lung cancer is the disease stage at diagnosis, thus developing an effective screening method for early diagnosis has been a long-term goal in lung cancer care. In the last decade, and based on the results of large clinical trials, lung cancer screening programs using low-dose computer tomography (LDCT) in high-risk individuals have been implemented in some clinical settings, however, this method has various limitations, especially a high false-positive rate which eventually results in a number of unnecessary diagnostic and therapeutic interventions among the screened subjects. By using complex algorithms and software, artificial intelligence (AI) is capable to emulate human cognition in the analysis, interpretation, and comprehension of complicated data and currently, it is being successfully applied in various healthcare settings. Taking advantage of the ability of AI to quantify information from images, and its superior capability in recognizing complex patterns in images compared to humans, AI has the potential to aid clinicians in the interpretation of LDCT images obtained in the setting of lung cancer screening. In the last decade, several AI models aimed to improve lung cancer detection have been reported. Some algorithms performed equal or even outperformed experienced radiologists in distinguishing benign from malign lung nodules and some of those models improved diagnostic accuracy and decreased the false-positive rate. Here, we discuss recent publications in which AI algorithms are utilized to assess chest computer tomography (CT) scans imaging obtaining in the setting of lung cancer screening.

Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein–Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case–control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07–2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22–3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC.

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD- or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34+CD38- AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ., Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V.

The loss of killer cell Ig-like receptor ligands (KIR-Ls) due to the copy number–neutral loss of heterozygosity of chromosome 6p (6pLOH) in leukocytes of patients with acquired aplastic anemia (AA) may alter the susceptibility of the affected leukocytes to NK cell killing in vivo. We studied 408 AA patients, including 261 who were heterozygous for KIR-Ls, namely C1/C2 or Bw6/Bw4, for the presence of KIR-L–missing [KIR-L(−)] leukocytes. KIR-L(−) leukocytes were found in 14 (5.4%, C1 [n = 4], C2 [n = 3], and Bw4 [n = 7]) of the 261 patients, in whom corresponding KIR(+) licensed NK cells were detected. The incidence of 6pLOH in the 261 patients (18.0%) was comparable to that in 147 patients (13.6%) who were homozygous for KIR-L genes. The percentages of HLA-lacking granulocytes (0.8–50.3%, median 15.2%) in the total granulocytes of the patients with KIR-L(−) cells were significantly lower than those (1.2–99.4%, median 55.4%) in patients without KIR-L(−) cells. KIR2DS1 and KIR3DS1 were only possessed by three of the 14 patients, two of whom had C2/C2 leukocytes after losing C1 alleles. The expression of the KIR3DS1 ligand HLA-F was selectively lost on KIR-L(−) primitive hematopoietic stem cells derived from 6pLOH(+) induced pluripotent stem cells in one of the KIR3DS1(+) patients. These findings suggest that human NK cells are able to suppress the expansion of KIR-L(−) leukocytes but are unable to eliminate them partly due to the lack of activating KIRs on NK cells and the low HLA-F expression level on hematopoietic stem cells in AA patients.

Despite duodenal-type follicular lymphoma (DTFL) being morphologically, immunophenotypically and genetically indistinguishable from nodal FL (nFL), this entity typically shows a significantly better prognosis. Here, we analysed the tumour immune microenvironments of diagnostic specimens from patients with DTFL (n = 30), limited-stage FL (LSFL; n = 19) and advanced-stage FL (ASFL; n = 31). The mean number of CD8+ tumour-infiltrating lymphocytes (TILs) in the neoplastic follicles was higher in DTFL (1,827/mm2 ) than in LSFL (1,150/mm2 ) and ASFL (1,188/mm2 ) (P = 0·002, P = 0·002, respectively). In addition, CD8+ PD1- T cells with non-exhausting phenotype were more abundant in the peripheral blood (PB) of DTFL than in LSFL and ASFL, indicating that DTFL may exhibit a better and longer-lasting T cell-mediated immune response. Moreover, whereas FOXP3+ CTLA-4+ effector regulatory T cells (eTregs) were rarely observed in the neoplastic follicles of DTFL (mean: 12/mm2 ), they were more abundant in LSFL (78/mm2 ) and ASFL (109/mm2 ) (P = 2·80 × 10-5 , P = 4·74 × 10-8 , respectively), and the numbers of eTregs correlated inversely with those of CD8+ TILs (r = -0267; P = 0·018). Furthermore, DTFL showed significantly fewer circulating FOXP3hi CD45RA- CD25hi eTregs (0·146%) than ASFL (0·497%) and healthy controls (0·639%) (P = 0·0003, P = 6·79 × 10-7 , respectively). These results suggest that the augmented anti-tumour immune reactions may contribute to a better prognosis on DTFL.

Heme oxygenase-1 (HO-1), an intracellular enzyme that catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exerts anti-inflammatory and cytoprotective effects against endothelial cell injury. The HO-1 promoter gene has one important single-nucleotide polymorphism (SNP) rs2071746 (-413A&gt, T) that is functional, and the A allele has been reported to be associated with higher HO-1 expression levels than the T allele. We investigated the influence of the HO-1 rs2071746 SNP on the transplant outcomes in 593 patients with hematological malignancies undergoing unrelated, human leukocyte antigen (HLA)-matched, T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. In patients with high-risk diseases, the donor A/A or A/T genotype was associated with better 5 year overall survival (35% vs. 25%, p = 0.03) and 5 year disease-free survival (35% vs. 22%, p = 0.0072), compared to the donor T/T genotype. These effects were not observed in patients with low-risk diseases. The current findings therefore indicate that HO-1 rs2071746 genotyping could be useful for selecting donors and tailoring transplant strategies for patients with high-risk hematologic malignancies.

We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.

Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA-) HSCs remain unknown. To address this issue, we generated induced pluripotent stem cells (iPSCs) from an AA patient who possessed HLA-B4002-lacking (B4002-) leukocytes. Three different iPSC clones (wild-type [WT], 6pLOH+, and B*40:02-mutant) were established from the patient's monocytes. Three-week cultures of the iPSCs in the presence of various growth factors produced hematopoietic cells that make up 50% to 70% of the CD34+ cells of each phenotype. When 106 iPSC-derived CD34+ (iCD34+) cells with the 3 different genotypes were injected into the femoral bone of C57BL/6.Rag2 mice, 2.1% to 7.3% human multilineage CD45+ cells of each HLA phenotype were detected in the bone marrow, spleen, and peripheral blood of the mice at 9 to 12 weeks after the injection, with no significant difference in the human:mouse chimerism ratio among the 3 groups. Stimulation of the patient's CD8+ T cells with the WT iCD34+ cells generated a cytotoxic T lymphocyte (CTL) line capable of killing WT iCD34+ cells but not B4002- iCD34+ cells. These data suggest that B4002- iCD34+ cells show a repopulating ability similar to that of WT iCD34+ cells when autologous T cells are absent and CTL precursors capable of selectively killing WT HSCs are present in the patient's peripheral blood.