Immune checkpoint blockade therapy has been successful in treating some types of cancers but has not shown clinical benefits for treating leukemia 1 . This result suggests that leukemia exploits unique escape mechanisms. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukemia cells. It remains unknown whether these receptors can initiate immune-related primary signaling in tumor cells. Here we show that LILRB4, an ITIM-containing receptor and a monocytic leukemia marker, supports tumor cell infiltration into tissues and suppresses T cell activity via ApoE/LILRB4/SHP-2/uPAR/Arginase-1 signaling axis in acute myeloid leukemia (AML) cells. Blocking LILRB4 signaling using knockout and antagonistic antibody approaches impeded AML development. Thus, LILRB4 orchestrates tumor invasion pathways in monocytic leukemia cells by creating an immune-suppressive microenvironment. LILRB4 represents a compelling target for treatment of monocytic AML.

Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3 À/À HSC that are defective in their activity. We show that Foxo3 À/À HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3 À/À hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3 À/À HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells.

To develop and validate a radiomics signature for the prediction of gastric cancer (GC) survival and chemotherapeutic benefits. In this multicenter retrospective analysis, we analyzed the radiomics features of portal venous-phase computed tomography in 1591 consecutive patients. A radiomics signature was generated by using the Lasso-Cox regression model in 228 patients and validated in internal and external validation cohorts. Radiomics nomograms integrating the radiomics signature were constructed, demonstrating the incremental value of the radiomics signature to the traditional staging system for individualized survival estimation. The performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. The radiomics signature consisted of 19 selected features and was significantly associated with DFS (disease-free survival) and OS (overall survival). Multivariate analysis demonstrated that the radiomics signature was an independent prognostic factor. Incorporating the radiomics signature into the radiomics-based nomograms resulted in better performance for the estimation of DFS and OS than the clinicopathological nomograms and TNM staging system, with improved accuracy of the classification of survival outcomes. Further analysis showed that stage II and III patients with higher radiomics scores exhibited a favorable response to chemotherapy. In conclusion, the newly developed radiomics signature is a powerful predictor of DFS and OS, and it may predict which patients with stage II and III GC benefit from chemotherapy.

Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types [1][2][3][4][5][6] . Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults [11][12][13] . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. RESULTSFasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14-22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25,26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation (Fig. 1a) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice (Fig. 1b,c). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks posttransplantation (Fig. 1c,d).Next, we measured the distribution of B lymphoblastic cells and myeloid cells in the GFP + compartment of the B-ALL mice. Control mice with B-ALL had 65-80% of B220 + cells (pan B lineage marker) and 0.5-2% of Mac-1 + cells (myeloid lineage marker) in GFP + fractions of PB, BM and SP (Fig. 1e,f), indicative of fully developed B-ALL. By contrast, there were only 19-28% of B220 + cells and 5-12% of Mac-1 + in GFP + fractions in fasted mice (Fig. 1e,f), consistent with loss of the B-ALL phenotype. There was also a higher percentage of New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered ...

Highlights d Disease-associated mutations endow SHP2 liquid-liquid phase separation capability d SHP2 LLPS is driven by electrostatic interactions mediated by PTP domain d SHP2 allosteric inhibitors block SHP2 LLPS by locking SHP2 in closed conformation d Mutant SHP2 can recruit and activate WT SHP2 in LLPS to promote MAPK activation

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TNM staging system of gastric cancer (GC) is not adequate for definition of prognosis and cannot predict the candidates who are likely to benefit from chemotherapy. In this research, we constructed a GC-SVM classifier integrating 3 clinicopathologic features and 8 IHC features in the training cohort of 251 patients. And further validation of the GC-SVM classifier was performed in two validation cohort of 535 patients.Multivariate analysis revealed that the GC-SVM classifier was an independent prognostic factor. Furthermore, the classifier had higher predictive accuracy for OS and DFS than TNM stage and can added prognostic value to the TNM staging system. Moreover, the GC-SVM classifier might be able to predict which patients will benefit from adjuvant chemotherapy. Thus, the classifier could facilitate patient counseling and individualized management. Conclusion:The newly developed GC-SVM classifier was a powerful predictor of OS and DFS. Moreover, the GC-SVM classifier could predict which patients with stage II and III GC benefit from adjuvant chemotherapy.

BackgroundAdult hematopoietic stem cells (HSCs) are maintained in a microenvironment, known as niche in the endosteal regions of the bone marrow. This stem cell niche with low oxygen tension requires HSCs to adopt a unique metabolic profile. We have recently demonstrated that mouse long-term hematopoietic stem cells (LT-HSCs) utilize glycolysis instead of mitochondrial oxidative phosphorylation as their main energy source. However, the metabolic phenotype of human hematopoietic progenitor and stem cells (HPSCs) remains unknown.ResultsWe show that HPSCs have a similar metabolic phenotype, as shown by high rates of glycolysis, and low rates of oxygen consumption. Fractionation of human mobilized peripheral blood cells based on their metabolic footprint shows that cells with a low mitochondrial potential are highly enriched for HPSCs. Remarkably, low MP cells had much better repopulation ability as compared to high MP cells. Moreover, similar to their murine counterparts, we show that Hif-1α is upregulated in human HPSCs, where it is transcriptionally regulated by Meis1. Finally, we show that Meis1 and its cofactors Pbx1 and HoxA9 play an important role in transcriptional activation of Hif-1α in a cooperative manner.ConclusionsThese findings highlight the unique metabolic properties of human HPSCs and the transcriptional network that regulates their metabolic phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0020-3) contains supplementary material, which is available to authorized users.