Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis.

Wnt/ß-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased ß-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/ß-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/ß-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of ß-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/ß-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates ß-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced ß-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced ß-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

Gene expression networks involved in multiple cellular programs coexist in individual hepatocellular cancer cells.

The gene expression networks of a single cell can be used to reveal cell type- and condition-specific patterns that account for cell states, cell identity, and its responses to environmental changes. We applied single cell sequencing datasets to define mRNA patterns and visualized potential cellular capacities among hepatocellular cancer cells. The expressing numbers and levels of genes were highly heterogenous among the cancer cells. The cellular characteristics were dependent strongly on the expressing numbers and levels of genes, especially oncogenes and anti-oncogenes, in an individual cancer cell. The transcriptional activations of oncogenes and anti-oncogenes were strongly linked to inherent multiple cellular programs, some of which oppose and contend against other processes, in a cancer cell. The gene expression networks of multiple cellular programs proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, ATP production, and neurogenesis coexisted in an individual cancer cell. The findings give rise a hypothesis that a cancer cell expresses balanced combinations of genes and undergoes a given biological process by rapidly transmuting gene expressing networks.

Identifying STRN3-RARA as a new fusion gene for acute promyelocytic leukemia.

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.

An integrated map of fibroblastic populations in human colon mucosa and cancer tissues.

Fibroblasts and myofibroblasts are major mesenchymal cells in the lamina propria of colon mucosa and in colon cancer tissues. Detailed insight into the highly specific populations of fibroblasts and myofibroblasts is required to understand the integrity and homeostasis of human colon mucosa and colon cancer. Based on gene expression profiles of single cells, we identified fibroblast populations that produce extracellular matrix components, Wnt ligand- and BMP-secreting fibroblasts, chemokine- and chemokine ligand-generating fibroblasts, highly activated fibroblasts, immune-modulating fibroblasts, epithelial cell-modulating myofibroblasts, stimuli-responsive myofibroblasts, proliferating myofibroblasts, fibroblast-like myofibroblasts, matrix producing myofibroblasts, and contractile myofibroblasts in human colon mucosa. In colon cancer tissue, the compositions of fibroblasts and myofibroblasts were highly altered, as were the expressing patterns of genes including BMPs, Wnt ligands, chemokines, chemokine ligands, growth factors and extracellular matrix components in fibroblasts and myofibroblasts. Our work expands the working atlas of fibroblasts and myofibroblasts and provides a framework for interrogating the complexity of stromal cells in human healthy colon mucosa and colon cancer tissues.

Prognostic value and biological function of LRRN4 in colorectal cancer.

BACKGROUND: Several nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear. METHODS: We examined the expression and clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry in a Chinese cohort. Furthermore, colony formation, flow cytometry, wound healing assays and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted coexpression network analysis, DAVID and western blot analysis were used to explore the potential molecular mechanism. RESULTS: We provide the first evidence that LRRN4 expression, at both the mRNA and protein levels, was remarkably high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K. LRRN4 knockdown resulted in downregulation of Akt, p-Akt, ERK1/2 and p-ERK1/2, the downstream of the Ras/MAPK signaling pathway, overexpression of LRRN4 leaded to the upregulation of these proteins. CONCLUSIONS: Our results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 regulating several malignant phenotypes of neoplastic cells via RAS/MAPK signal pathways.

Red blood cells are damaged by intraoperative blood salvage via Ca2+-dependent and -independent mechanisms.

AIMS: Intraoperative blood salvage (IBS) is associated with shortened lifespan of red blood cells (RBCs). This study aims to examine how salvaged RBCs are compromised during IBS. MAIN METHODS: Thirty patients who underwent vertebra surgery with IBS were included in the study. To examine possible mechanisms of IBS-induced injury, both fresh and salvaged RBCs from each patient were mixed with plasma, the Ca2+ ionophore ionomycin or mannitol-adenine-phosphate (MAP) solution (n = 10 patients per condition). Binding of Fluo-3 and/or Annexin V by RBCs was measured. KEY FINDINGS: The percentage of Fluo-3-binding RBCs in salvaged samples was 2.83 ±â€¯0.76%, which increased to 15.34 ±â€¯5.99% after 48-h incubation in plasma. These percentages were significantly higher than those observed with fresh RBCs (P < 0.01). Ionomycin dose-dependently increased the percentage of Fluo-3-binding RBCs in salvaged samples, while MAP solution decreased it. Incubating salvaged RBCs in plasma for 48 h increased the percentage of Fluo-3-positive spherocytes from 0.8 ±â€¯0.6% to 11.35 ±â€¯3.96%, and this increase was blocked by MAP solution. Ionomycin increased the percentage of RBCs binding both Fluo-3 and Annexin V, while MAP decreased this percentage. The percentage of Annexin V-binding RBCs was also higher in salvaged samples than in fresh samples, but this percentage was unaffected by either ionomycin or MAP solution. SIGNIFICANCE: Our results suggest that IBS induces a postponed RBC damage by inducing spherocyte formation, which likely reflects Ca2+ entry induced by energy exhaustion, as well as by exposing phosphatidylserine on the RBC surface, which likely occurs via Ca2+ entry and via Ca2+-independent pathways.

Mid1ip1b modulates apical reorientation of non-centrosomal microtubule organizing center in epithelial cells.

In most kinds of animal cells, the centrosome serves as the main microtubule organizing center (MTOC) that nucleates microtubule arrays throughout the cytoplasm to maintain cell structure, cell division and intracellular transport. Whereas in epithelial cells, non-centrosomal MTOCs are established in the apical domain for generating asymmetric microtubule fibers and cilia in epithelial cells for the organ morphogenesis during embryonic development. However, the mechanism by which MTOCs localize to the apical domain in epithelial cells remains largely unknown. Here, we show that Mid1ip1b has a close interaction with γ-tubulin protein, the central component of MTOC, and modulates lumen opening of the neural tube, gut, intestine, and kidney of zebrafish. Knockdown or dominant negative effect of Mid1ip1b resulted in failure of lumen formation of the organs as aforementioned. Moreover, the non-centrosomal MTOCs were unable to orientate to the apical domain in Mid1ip1b knockdown epithelial cells, and the centrosomal MTOCs were inaccurately placed in the apical domain, resulting in defective formation of asymmetric microtubules and misplacement of cilia in the apical domain. These data uncover a molecule that controls the proper localization of MTOCs in the apical domain in epithelial cells for organ morphogenesis during embryonic development.

Neurons generated from carcinoma stem cells support cancer progression.

Recent evidences show that nervous system acts as a crucial part of cancer microenvironment. Infiltration of nerve fibers into cancer microenvironment has an important active role in cancer progression. The stimulations of both cancer growth and metastasis by members of nervous system such as neurons and glial cells have been demonstrated. However, how the nervous system is built in cancer is largely unknown. Here we show that a fraction of cancer stem cells (CSCs) derived from patients with gastric carcinoma and colorectal carcinoma are capable of producing neurons that are involved in tumor neurogenesis and tumor growth. Cancer stem cell monoclone derived from a single cancer stem cell was able to generate neurons including sympathetic and parasympathetic neurons to take part in the nervous system in cancer tissues. Knocking down the neural cell generating capability of the human CSCs inhibited the growth of xenograft tumors in mouse model. Our data demonstrate that human CSCs are able to produce one of most important components in the cancer microenvironment that are required for cancer development and progression.

Prognostic value of CD133+ CD54+ CD44+ circulating tumor cells in colorectal cancer with liver metastasis.

In the previous study, we had showed the expression of CD133+ CD54+ CD44+ cellular subpopulation of circulating tumor cells (CTCs) was significantly associated with liver metastasis of colorectal cancer (CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients (P < 0.001). The liver metastatic CRC patients with high expression of CD133+ CD54+ (P < 0.001), CD133- CD54+ (P = 0.004), and CD133+ CD44+ CD54+ (P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [HR] = 3.056; 95% confidence interval [CI] = 1.354-6.897; P = 0.007), treatment strategy (HR = 0.212; 95% CI = 0.056-0.808; P = 0.023), and CD133+ CD44+ CD54+ cellular subpopulation of CTCs (HR = 6.459; 95% CI = 1.461-28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133+ CD44+ CD54+ cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis.

Intraoperative blood salvage may shorten the lifespan of red blood cells within 3 days postoperatively: A pilot study.

BACKGROUND: Intraoperative blood salvage (IBS) recovers most lost blood, and is widely used in the clinic. It is unclear why IBS does not reduce long-term postoperative requirements for red blood cells (RBCs), and 1 possibility is that IBS affects RBC lifespan. METHODS: Prospectively enrolled patients who underwent spine, pelvic, or femur surgery not involving allogeneic RBC transfusion were grouped based on whether they received IBS or not. Volumes of blood lost and of RBCs salvaged during surgery were recorded. Total blood cell counts, levels of plasma-free hemoglobin, and CD235a-positive granulocytes were determined perioperatively. RESULTS: Although intraoperative blood loss was higher in the IBS group (n = 45) than in the non-IBS group (n = 52) (P < .001), hemoglobin levels were similar between groups (P = .125) at the end of surgery. Hemoglobin levels increased in non-IBS patients (4 ±â€Š11 g/L), but decreased in IBS patients (-7 ±â€Š12 g/L) over the first 3 postoperative days. Nadir hemoglobin levels after surgery were higher in the non-IBS group (107 ±â€Š12 g/L) than in the IBS group (91 ±â€Š12 g/L). Salvaged RBC volume correlated with hemoglobin decrease (r = 0.422, P = .004). In multivariate analysis, salvaged RBC volume was an independent risk factor for hemoglobin decrease (adjusted odds ratio 1.002, 95% confidence interval 1.001-1.004, P = .008). Flow cytometry showed the numbers of CD235a-positive granulocytes after surgery to be higher in the IBS group than in the non-IBS group (P < .05). CONCLUSION: IBS may shorten the lifespan of RBCs by triggering their engulfment upon re-infusion (China Clinical Trial Registry ChiCTR-OCH-14005140).

Endothelium originated from colorectal cancer stem cells constitute cancer blood vessels.

Tumor growth depends on the formation of blood vessels that provide the supply of nutrients and oxygen. Previous data have shown that glioblastoma stem cells are able to give rise to vascular cells to constitute the functional vessels in tumor tissues. However, which kinds of vascular cells are generated from glioblastoma stem cells is largely debated. In addition, there is little evidence showing that the stem cells from other kinds of tumors can produce vascular cells to constitute the functional blood vessels in tumor tissues. Here we show that cancer stem cells of human colorectal carcinomas (CoCSC) can give rise to vascular endothelial cells and compose the vasculatures in cancer tissues. The human-cell-specific nuclear antigen NuMA+ vascular endothelial cells were detected in the blood vessels in xenografts derived from CoCSC. NuMA+ endothelial cells incorporated into functional blood vessels. Our data indicate that the cancer stem cells derived from human colorectal carcinomas have the capacity to generate functional blood vessels and provide a new mechanism for tumor vasculogenesis in carcinoma.

Platelets protect lung from injury induced by systemic inflammatory response.

Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-ß and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses.

MicroRNA-184 Modulates Human Central Nervous System Lymphoma Cells Growth and Invasion by Targeting iASPP.

Central nervous system lymphoma (CNSL) remains a diagnostical and therapeutical challenge. MiRNAs post-transcriptionally regulate expression of targeted mRNAs through binding to their 3' UTR to inhibit their translation or promote their degradation. Oncoprotein inhibitory member of the ASPP family (iASPP), a key inhibitor of tumor suppressor p53, has been reported to play oncogenic role in cancers. Our present study was aimed to determine whether the miR-184/iASPP axis is involved in the proliferation and invasion of CNSL. A reduced level of miR-184 was observed in CNSL tissues. Exogenous miR-184 inhibited cell survival and invasion, as well as the tumor volumes, while miR-184 inhibition could reverse this process. The RNA and protein levels of iASPP were significantly inhibited by miR-184, and the 3' UTR of iASPP was shown to be a target of miR-184. The expression of iASPP was up-regulated in CNSL tissues, compared to that of the normal brain tissues. The inhibition of iASPP by shRNA iASPP significantly repressed CNSL cells' proliferation and invasion, and reduced the volume of the tumor. Besides, iASPP overexpression could partly restore the suppressive effect of miR-184 on CNSL cell proliferation and invasive capability. We also revealed that miR-184/iASPP axis regulated the proliferation and invasion via PI3K/Akt signaling pathway, which presents a novel potential therapy for intervention of CNSL. Taken together, our findings revealed the detailed role of the miR-184/iASPP axis in CNSL and this axis might modulate the proliferation and invasion of CNSL via regulating the PI3K/Akt signaling pathway. J. Cell. Biochem. 118: 2645-2653, 2017. © 2017 Wiley Periodicals, Inc.

CD133+CD54+CD44+ circulating tumor cells as a biomarker of treatment selection and liver metastasis in patients with colorectal cancer.

INTRODUCTION: Liver is the most common site of distant metastasis in colorectal cancer (CRC). Early diagnosis and appropriate treatment selection decides overall prognosis of patients. However, current diagnostic measures were basically imaging but not functional. Circulating tumor cells (CTCs) known as hold the key to understand the biology of metastatic mechanism provide a novel and auxiliary diagnostic strategy for CRC with liver metastasis (CRC-LM). RESULTS: The expression of CD133+ and CD133+CD54+CD44+ cellular subpopulations were higher in the peripheral blood of CRC-LM patients when compared with those without metastasis (P<0.001). Multivariate analysis proved the association between the expression of CD133+CD44+CD54+ cellular subpopulation and the existence of CRC-LM (P<0.001). The combination of abdominal CT/MRI, CEA and the CD133+CD44+CD54+ cellular subpopulation showed increased detection and discrimination rate for liver metastasis, with a sensitivity of 88.2% and a specificity of 92.4%. Meanwhile, it also show accurate predictive value for liver metastasis (OR=2.898, 95% C.I.1.374-6.110). MATERIALS AND METHODS: Flow cytometry and multivariate analysis was performed to detect the expression of cancer initiating cells the correlation between cellular subpopulations and liver metastasis in patients with CRC. The receiver operating characteristic curves combined with the area under the curve were generated to compare the predictive ability of the cellular subpopulation for liver metastasis with current CT and MRI images. CONCLUSIONS: The identification, expression and application of CTC subpopulations will provide an ideal cellular predictive marker for CRC liver metastasis and a potential marker for further investigation.

Development-associated immunophenotypes reveal the heterogeneous and individualized early responses of adult B-acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B-ALL) exhibits phenotypes reminiscent of normal stages of B-cell development. As demonstrated by flow cytometry, the immunophenotypes are able to determine the stages of B cell development. Multicolor flow cytometry (MFC) is more accurate at identifying cell populations. In this study, 9-color panels, including CD10, CD19, CD20, CD22, CD34, CD79a, CD179a, and IgM, which are sequentially expressed during B cell development, were designed to detect the leukemia cell subpopulations in adult B-ALL patients. In 23 patients at diagnosis, 192 heterogeneous subpopulations of leukemia cells were detected. Compared with their counterparts at diagnosis and after the 1st course of induction therapy, the responses of the subpopulations were also heterogeneous. In the CD10 population, the residual B cell subpopulations in the BCR/ABL patients were obviously reduced compared to those in the BCR/ABL patients. New subpopulations were detected in 22 of 23 patients and were primarily located in the CD34CD10 populations. Subpopulations of clonal evolution were heterogeneous after induction therapy. Our results suggest that the subpopulations in B-ALL patients should be dynamically monitored by development-associated immunophenotyping before, during, and after induction therapy and to predict the prognosis of the disease.

Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity.

Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4(+) and CD8(+) T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4(+) and CD8(+) effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8(+) effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens.

Lentivirus mediated RNA interference of EMMPRIN (CD147) gene inhibits the proliferation, matrigel invasion and tumor formation of breast cancer cells.

BACKGROUND: Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147), a glycoprotein enriched on the plasma membrane of tumor cells, promotes proliferation, invasion, metastasis, and survival of malignant tumor cells. In this study, we sought to examine the expression of EMMPRIN in breast tumors, and to identify the potential roles of EMMPRIN on breast cancer cells. METHODS: EMMPRIN expression in breast cancer tissues was assessed by immunohistochemistry. We used a lentivirus vector-based RNA interference (RNAi) approach expressing short hairpin RNA (shRNA) to knockdown EMMPRIN gene in breast cancer cell lines MDA-MB-231 and MCF-7. In vitro, Cell proliferative, invasive potential were determined by Cell Counting Kit (CCK-8), cell cycle analysis and matrigel invasion assay, respectively. In vivo, tumorigenicity was monitored by inoculating tumor cells into breast fat pad of female nude mice. RESULTS: EMMPRIN was over-expressed in breast tumors and breast cancer cell lines. Down-regulation of EMMPRIN by lentivirus vector-based RNAi led to decreased cell proliferative, decreased matrigel invasion in vitro, and attenuated tumor formation in vivo. CONCLUSION: High expression of EMMPRIN plays a crucial role in breast cancer cell proliferation, matrigel invasion and tumor formation.

Differential Expression Profile of Immunological Cytokines in Local Ovary in Patients with Polycystic Ovarian Syndrome: analysis by Flow Cytometry.

OBJECTIVE: Immune dysregulation may play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). The purpose of this study was to investigate the Th1 and Th2-related cytokine profile in local ovary of women with PCOS. STUDY DESIGN: The T lymphocytes of follicular fluid (FF) were obtained at the time of oocyte retrieval before in-vitro fertilization (IVF) in woman with or without PCOS. After culturing with PMA, Ionomycin and Golgi stop agent, cells were detected for the intracellular cytokine production by flow cytometry. The profile of Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-10) cytokines of CD3(+) CD4(+)T lymphocyte subsets were analyzed through invert gating. These cytokines in FF were also evaluated by ELISA. RESULTS: Flow cytometry analysis showed that the production of Th1 (IFN-γ, IL-2) cytokines in FF lymphocytes in PCOS patients were significantly higher than those in controls; ELISA result also demonstrated that the concentration of Th1 cytokines (IFN-γ, IL-2) in FF in PCOS patients is significantly increased compared with those in controls. CONCLUSION: It is concluded that the immune dominance of Th1 may be the immunological feature of the ovary in PCOS patients. It might participate in the immune pathogenesis in the ovary of PCOS patients. These results suggest that chronic inflammation maybe one of the underlying mechanism for the pathogenesis of PCOS.

Tanshinone IIA inhibits acute promyelocytic leukemia cell proliferation and induces their apoptosis in vivo.

Tanshinone IIA (TanIIA) is a traditional Chinese agent and has been widely used for treatment of cardiovascular diseases. Our previous study has shown that TanIIA can induce the differentiation of acute promyelocytic leukemia (APL) cells by increasing C/EBPß expression and induce APL cell apoptosis in vitro. In this study, we evaluated the activity of TanIIA against APL in vivo. We found that treatment with TanIIA prevented APL-mediated reduction in body weights. Treatment with TanIIA inhibited the proliferation of APL cells and triggered APL cell apoptosis and differentiation in vivo. Treatment with TanIIA significantly prolonged the survival of APL-bearing mice. Our data indicate that TanIIA has potent anti-APL activity with little adverse effect.