Abro1 maintains genome stability and limits replication stress by protecting replication fork stability.

Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chromosome instability, and Abro1-null mice are tumor-prone. We show that Abro1 protects stalled replication fork stability by inhibiting DNA2 nuclease/WRN helicase-mediated degradation of stalled forks. Depletion of RAD51 prevents the DNA2/WRN-dependent degradation of stalled forks in Abro1-deficient cells. This mechanism is distinct from the BRCA2-dependent fork protection pathway, in which stable RAD51 filament formation prevents MRE11-dependent degradation of the newly synthesized DNA at stalled forks. Thus, our data reveal a new aspect of regulated protection of stalled replication forks that involves Abro1.

SOX11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma or Large B-Cell Lymphoma?

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin D1+ blastoid/pleomorphic MCL but different from DLBCL. Principal component analysis revealed that the cohort cases overlapped with cyclin D1+ blastoid/pleomorphic MCL but had minimal overlap with DLBCL. All patients in the cohort had clinicopathologic features similar to those reported for patients with cyclin D1+ MCL. We also performed a survey of SOX11 expression in a group of 85 cases of DLBCL and 24 cases of blastoid HGBL. SOX11 expression showed a 100% specificity and positive predictive value for the diagnosis of MCL. Overall, the results support the conclusion that large or blastoid B-cell neoplasms that are positive for SOX11 are best classified as cyclin D1-negative blastoid/pleomorphic MCL, and not as DLBCL or blastoid HGBL. We also conclude that SOX11 is a specific marker for the diagnosis of MCL, including cyclin D1-negative blastoid/pleomorphic MCL cases and should be performed routinely on blastoid/large B-cell neoplasms to help identify potential cases of cyclin D1-negative blastoid/pleomorphic MCL.

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Integrated clinical genotype-phenotype characteristics of early T-cell precursor acute lymphoblastic leukemia.

BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood. METHODS: The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL. RESULTS: The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1-2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next-generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi-agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. CONCLUSIONS: Patients with ETP-ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers.

ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.

BACKGROUND: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. METHODS: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms. RESULTS: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow-up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. CONCLUSIONS: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease-specific and should be interpreted with caution to classify myeloid neoplasms.

Over expression of ubiquitin-conjugating enzyme E2O in bone marrow mesenchymal stromal cells partially attenuates acute myeloid leukaemia progression.

Bone marrow mesenchymal stromal cells (BM-MSCs) are implicated in the pathogenesis of acute myeloid leukaemia (AML). However, due to the high heterogeneity of AML the mechanism underlying the cross-talk between MSCs and leukaemia cells is not well understood. We found that mixed-lineage leukaemia-AF9 (MLL-AF9)-induced AML mice-derived MSCs had higher proliferative viability compared to wild-type mice-derived MSCs with ubiquitin-conjugating enzyme E2O (Ube2o) down-regulation. After overexpression of UBE2O in AML-derived MSCs, the growth capacity of MSCs was reduced with nuclear factor kappa B subunit 1 (NF-κB) pathway deactivation. In vitro co-culture assay revealed that UBE2O-overexpression MSCs suppressed the proliferation and promoted apoptosis of AML cells by direct contact. In vivo results revealed that the leukaemia burden was reduced and the overall survival of AML mice was prolonged, with decreased dissemination of leukaemia cells in BM, spleen, liver and peripheral blood. Additionally, subcutaneous tumorigenesis revealed that tumour growth was also suppressed in the UBE2O-overexpression MSCs group. In conclusion, UBE2O was expressed at a low level in MLL-AF9-induced AML mice-derived MSCs. Overexpression of UBE2O in MSCs suppressed their proliferation through NF-κB pathway deactivation, which resulted in AML suppression. Our study provides a theoretical basis for a BM microenvironment-based therapeutic strategy to control disease progression.

Efficacy of Autologous Hematopoietic Stem Cell Transplantation versus Chemotherapy or Allogeneic Hematopoietic Stem Cell Transplantation for Follicular Lymphoma: Systematic Review and Meta-Analysis.

BACKGROUND: The effect of autologous hematopoietic stem cell transplantation (auto-HSCT) versus conventional chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the survival of patients with advanced follicular lymphoma (FL) is uncertain. OBJECTIVES: To elucidate this, FL and HSCT were used as keywords to search in PubMed, Embase, Web of Science, and Cochrane Library databases. METHOD: After data extraction and quality evaluation, a total of 13 studies were included, seven of which compared auto-HSCT with conventional chemotherapy and the other six compared allo-HSCT with auto-HSCT to the survival of FL patients. RESULTS: The results showed that auto-HSCT improved overall survival (OS), progression-free survival, and event-free survival of FL patients compared with conventional chemotherapy without auto-HSCT. Compared with allo-HSCT, the patients receiving auto-HSCT had longer OS and lower non-recurrent mortality. CONCLUSIONS: Auto-HSCT can provide a survival advantage for patients with FL compared with conventional chemotherapy and allo-HSCT did not result in a survival benefit.

LMO2 expression is frequent in T-lymphoblastic leukemia and correlates with survival, regardless of T-cell stage.

T- lymphoblastic leukemia/lymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 (15%) medullary type. LMO2 expression was present in 50 (74.6%) initial biopsies with an average of 87% positive tumor cells (range 30-100%). LMO2 expression in ETP, medullary and cortical T-LLs was not statistically different. In patients with biopsies after initial therapy, LMO2 expression was stable. LMO2 expression was associated with longer OS (p = 0.048) regardless of T-lymphoblast stage or other clinicopathologic features. These findings indicate that LMO2 is a promising new prognostic marker that could predict patients' outcomes and potentially be targeted for novel chemotherapy, i.e. PARP1/2 inhibitors, which have been shown to enhance chemotherapy sensitivity in LMO2 expressing diffuse large B cell lymphoma (DLBCL) tumors by decreasing DNA repair efficiency.

Blastoid high-grade B-cell lymphoma initially presenting in bone marrow: a diagnostic challenge.

The 2016 WHO classification introduced the category of high-grade B-cell lymphoma (HGBL), which includes one poorly understood subset, blastoid-HGBL. Establishing the diagnosis and distinguishing blastoid-HGBL from B-acute lymphoblastic leukemia (B-ALL) in bone marrow can be challenging. We assessed 31 cases of blastoid-HGBL diagnosed initially in bone marrow and compared this group to 36 cases of B-ALL using immunophenotyping, fluorescence in situ hybridization, and targeted next generation sequencing analysis. The 31 blastoid-HGBL cases included 14 HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma, DHL), 13 HGBL, not otherwise specified (NOS), and four cases with TdT expression that were difficult to classify. Compared with B-ALL, blastoid-HGBL cases more often showed increased intensity/bright expression of CD20, CD38, CD45, BCL-6, and MYC, and less frequent bright expression of CD10 and TdT. Cases of blastoid-HGBL also more frequently had MYC rearrangement, a complex karyotype and TP53 mutation (p < 0.01). With the exception of CD34, no other single factor, including TdT, was sensitive or adequately specific to distinguish blastoid-HGBL from B-ALL. We developed a scoring system using six distinctive features between 16 cases of unequivocal blastoid HGBL and 22 cases of CD34-positive B-ALL, with a score of ≥3 defining blastoid-HGBL. The system was further validated by using 15 cases of surface light chain negative, and/or CD45 dim to negative blastoid-HGBL and 14 cases of CD34-negative B-ALL. The sensitivity, specificity, positive, and negative predictive value of this scoring system were 100%, 94%, 94%, and 100%, respectively. Using this system, the four cases with TdT expression were all classified as blastoid-HGBL: three were DHL and one was HGBL-NOS. In conclusion, blastoid-HGBL shows distinctive immunophenotypic, cytogenetic, and molecular features as compared with B-ALL. The proposed scoring system can be helpful for the classification of diagnostically challenging blastoid lymphoid tumors presenting initially in the bone marrow.

Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.

Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations.

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.

Novel myeloperoxidase-derived HLA-A2-restricted peptides as therapeutic targets against myeloid leukemia.

BACKGROUND AIMS: Human myeloperoxidase has been shown to be overexpressed in many types of leukemia, such as chronic myeloid leukemia, acute myeloid leukemia and myelodysplastic syndrome. The authors identified two myeloperoxidase-derived HLA-A2-restricted peptides, MY4 and MY8, as novel leukemia-associated antigens. METHODS: Ex vivo-elicited MY4- and MY8-specific cytotoxic T lymphocytes were generated, and tested for leukemia cell lysis in vitro and in NOD/SCID AML xenograft model. RESULTS: These MY4- and MY8-specific cytotoxic T lymphocytes killed leukemic blasts while sparing healthy donor bone marrow cells. In addition, co-injection of MY4- and MY8-specific cytotoxic T lymphocytes into nonobese diabetic/severe combined immunodeficiency mice with acute myeloid leukemia drastically reduced tumor burden in vivo. The authors also found that MY4- and MY8-specific T cells could be detected in the peripheral blood mononuclear cells of allogeneic stem cell transplant recipients. CONCLUSIONS: These antigen-specific T cells were significantly increased in blood samples from patients compared with healthy donors, suggesting that both MY4 and MY8 are immunogenic and that MY4- and MY8-specific cytotoxic T lymphocytes may play a role in reducing leukemia in vivo. Thus, the discovery of MY4 and MY8 as novel leukemia-associated antigens paves the way for targeting these antigens in immunotherapy against myeloid leukemia.

PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma.

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3Tyr705) (r = 0.8, p < 0.0001). In contrast, the PD-L1/pSTAT3 correlation was weaker in ALK+ anaplastic large cell lymphoma (r = 0.4, p = 0.08). In ALK- anaplastic large cell lymphoma, the PD-L1+ subgroup was more often EMA positive (69% vs 20%, p = 0.02) and tended to be less often CD2+ (50% vs 83%, p = 0.059). In ALK+ anaplastic large cell lymphoma, PD-L1 was not associated with pathologic features (all p > 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

High levels of immunoglobulin expression predict shorter overall survival in patients with acute myeloid leukemia.

OBJECTIVES: It has been believed that immunoglobulins can only be produced by B lymphocytes and plasma cells. We have previously reported that IgG can be expressed in myeloblasts from patients with acute myeloid leukemia (AML) and plays a role in the proliferation and apoptosis of leukemic cells. However, its clinical impact has not been assessed. METHODS: We assessed the expression of different classes of immunoglobulin in peripheral blood and bone marrow samples from 132 AML patients and correlated the levels of expression with clinicopathologic and molecular genetic features, as well as clinical outcome. RESULTS: We found that, in addition to IgG, all classes of immunoglobulin are expressed in myeloblasts, including IgG, IgM, IgA, IgD, IgE, Igκ, and Igλ. The levels of IgG expression (coupled with Igκ or Igλ) are higher than those of IgM, IgA, IgD, and IgE. Using receiver operating characteristic (ROC) curve analysis, we identified two distinct groups of AML patients with differential expression of immunoglobulin and different clinical outcomes. CONCLUSIONS: High levels of immunoglobulin expression are associated with monocytic differentiation, multilineage dysplasia, TET2 and KRAS mutations, and poor overall survival. Assessment of immunoglobulin may serve as a useful marker for prognostic stratification and target therapy.

The Role of Tumor-Associated Macrophages in Leukemia.

In addition to intrinsic factors, leukemia cell growth is influenced by the surrounding nonhematopoietic cells in the leukemic microenvironment, including fibroblasts, mesenchymal stem cells, vascular cells, and various immune cells. Despite the fact that macrophages are an important component of human innate immunity, tumor-associated macrophages (TAMs) have long been considered as an accomplice promoting tumor growth and metastasis. TAMs are activated by an abnormal malignant microenvironment, polarizing into a specific phenotype and participating in tumor progression. TAMs that exist in the microenvironment of different types of leukemia are called leukemia-associated macrophages (LAMs), which are reported to be associated with the progression of leukemia. This review describes the role of LAMs in different leukemia subtypes.

EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis.

Many types of human tumor cells have overexpressed pyruvate kinase M2 (PKM2). However, the mechanism underlying this increased PKM2 expression remains to be defined. We demonstrate here that EGFR activation induces PLCγ1-dependent PKCε monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKCε interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCε phosphorylates IKKß at Ser177 and activates IKKß. Activated RelA interacts with HIF1α, which is required for RelA to bind the PKM promoter. PKCε- and NF-κB-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKKß activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-κB by EGF, in contrast to TNF-α, and the importance of the metabolic cooperation between the EGFR and NF-κB pathways in PKM2 upregulation and tumorigenesis.

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.

The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.

Kidney Injury in Murine Models of Hematopoietic Stem Cell Transplantation.

Acute graft-versus-host disease (GVHD) affects different organs, including the skin, liver, and gastrointestinal tract. Although kidneys are not among the organs commonly known to be the target of acute GVHD, kidney damage is frequently reported after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have studied the effect of bone marrow transplantation (BMT) on the kidneys in different murine models of GVHD. We found that glomerular damage in the kidneys is a common pathological finding in mice after BMT. The histopathological features of glomeruli damage included mesengiolysis, mesangial proliferation and edema, subendothelial and endothelial thickening, splitting of capillary walls in glomeruli, narrowing and collapsing of capillary lumens, fibrinoid necrosis of afferent arterioles, intimal hyperplasia, and microthrombi. These pathological features are similar to those detected in kidneys of patients with thrombotic microangiopathy (TMA) after allo-HSCT. We previously showed that activation of the complement system plays a role in GVHD-induced tissue injury in mice. Here we report the presence of complement activation products in the kidney specimens of mice after BMT. We also report that complement deficiency reduced the extent and severity of post-BMT glomerular damage in mice. We conclude that BMT in mice is associated with glomerular injury and tubulointerstitial nephritis, and that kidney damage is at least partially mediated by activation of the complement system.