SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.

The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.

Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma.

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

[Research on the expression of c-myc mRNA in ameloblastoma].

PURPOSE: To study the expression of c-myc mRNA in ameloblastoma (AB) and odontogenic keratocyst (OKC) and to investigate the genesis, development and biological characteristics of AB and OKC. METHODS: We detected c-myc mRNA in 54 cases of AB (31 primary ABs, 19 recurrent Abs and 4 malignant ABs), 16 cases of OKC and 7 cases of normal oral mucosa (NOM) by in situ hybridization. Chi2 test was used to analyze the results. RESULTS: The positive rate of AB, OKC and NOM was 81.5% (44/54), 75.0% (12/16) and 14.3% (1/7), respectively. There was statistical difference among three groups (chi2=15.488, P<0.05). Comparing the expression of primary AB (71.0%) with recurrent (94.7%), malignant AB (100.0%), there was a significant statistical difference (chi2=16.912, P<0.05). CONCLUSIONS: The expression of c-myc is important to the genesis and development of AB; following the change of primary, recurrent and malignant AB, the expression of c-myc mRNA increased significantly.It is suggested that c-myc mRNA may be an effective marker to evaluate the prognosis of AB.

[Expression of pRb and E2F-1 and telomerase activity in ameloblastoma].

OBJECTIVE: To investigate the expression of pRb and E2F-1, and the association between their expression and the activity of telomerase (hTERT) or cyclin E in human ameloblastoma (AB), and to explore the clinical biological characteristics of AB. METHODS: The expressions of pRb, E2F-1, cyclin E and hTERT mRNA in human AB were detected by in situ hybridization or immunohistochemistry (SP method). RESULTS: The positive expression ratio of pRb in the cell nucleus of AB was 20.4% (11/54). The positive ratio of E2F-1, cyclin E and hTERT mRNA was 92.6% (50/54), 66.7% (36/54) and 94.4% (51/54), respectively. With AB recurrence and malignant transformation, the expression of hTERT, E2F-1, cyclin E was up-regulated. hTERT and cyclin E or E2F-1 mRNA had high positive relation (Spearsman'r(s) = 1.000, P = 0.0001). CONCLUSIONS: The regulatory pathway of Rb/E2F-1 is associated with the cell proliferation and in differentiation of AB. The activity or release of telomerase may be related to the lower expression of Rb and higher expression of E2F-1, and is up-regulated in G(1) late phase by cyclin E.

[The study of the invasive biologic behavior of ameloblastoma].

OBJECTIVE: To investigate the invasive biologic behavior of ameloblastoma (AB) and to analyze its correlative factors. METHODS: The specimens of 43 cases of AB (primary AB 16 cases, recurrent AB 21 cases, malignant AB 6 cases) were examined immunohistochemically using the streptavidin-biotin method to determine the expression of E-cadherin (E-cad), matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor (VEGF). RESULTS: The cells in malignant AB scattered more, grew invasively, and the basal membrane ruptured or lost. The expression of E-cad in AB descended, MMP-2 and MMP-9 were strongly expressed in the epithelia cells of 28/41, 30/43 cases of AB, respectively. The positive rate and intensity of VEGF increased as AB recurred and transformed malignantly. The expression of E-cad, MMP-9 and VEGF were related to recurrence or malignant transformation of AB (r(s) = 0.309, 0.519, 0.381, P < 0.05). CONCLUSION: AB is a high invasive tumor. The biological behavior of AB is related to lost or abnormal expression of E-cad, the high expression of MMP-2, MMP-9, and VEGF.

[Expression of telomerase activity and c-myc and stimulatory protein 1 in human ameloblastoma].

OBJECTIVE: To study the oncogene transcriptor c-myc, stimulatory protein 1 (SP1) expression in ameloblastoma (AB) and their relation with telomerase reverse transcripase (hTERT), and to investigate the clinical biological characteristics of AB. METHODS: The expression was observed in AB by in situ hybridization and SP method. RESULTS: The positive rates of c-myc mRNA, hTERT mRNA and SP1 protein were 81.5% (44/54), 94.4% (51/54) and 83.3% (45/54), respectively. Their positive rates increased as AB recurred and transformed malignantly. A strong correlation was found between hTERT and c-myc, hTERT and SP1 (rs = 0.853, P < 0.001; rs = 0.900, P < 0.001). CONCLUSION: Activity of telomerase plays an important role in the tumorigenesis development of AB. Increasing of hTERT expression may be related to c-myc and SP1. The expression of these three parameters has a significant correlation with the clinical biological characteristics of AB.

[Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase in ameloblastoma].

OBJECTIVE: To study the expression of matrix metalloproteinase(MMP) and tissue inhibitor of metalloproteinase (TIMP) in ameloblastoma (AB) and to determine the relationship between biological behavior of AB and clinical pathology. METHODS: The specimens of 43 cases of AB, 10 cases of odontogenic keratocyst (OKC), 8 cases of normal oral mucosa were examined by streptavidin-biotin method. RESULTS: In 8 cases of normal oral epithelial, MMP-2 was negative or weak positive. In OKC, MMP-2 was extensively positive in stratum spinosum of 2 cases, and weekly or negative in stratum basale. MMP-2 was strongly expressed in the central and peripheral cells of the tumor islands in 28 cases of AB. There were difference among these three groups (P < 0.001). Comparing AB with normal oral mucosa and OKC, there was significant difference (P < 0.05). MMP was positive expressed in cells of stroma. The positively rate and intensity increased as AB recurrence and transformed malignantly, but were not associated with age, sex, pathological type and location. TIMP-1 was weakly or not expressed in normal oral mucosa, stoma, OKC and AB. CONCLUSIONS: The high expression of MMP-2 and MMP-9 is related to the biological behavior of AB. Imbalances of the expression of MMP-2 and MMP-9 protein maybe be one of the facts of the invasion of AB. The MMPs activation produced by stromal cells may be also be related to the invasion of AB.