The combination of PRL-3 inhibitor with sorafenib synergistically promotes AML apoptosis.

Phosphatase of regenerating liver-3 (PRL-3) is recognized as a novel independent crucial driver for AML progression. Thus, the specific inhibitor of PRL-3 would be a potential therapeutic agent to AML in clinics, but there are not enough preclinical applications reported yet. Here we evaluated the cytotoxicity of PRL-3 inhibitor, BR-1, against AML cells ML-1 and MOLM-13. Meanwhile, the effect of BR-1 on the biological characteristics of AML cells and the underlying mechanism was investigated along with the combination of BR-1 and sorafenib on the AML cell viability. Our results show that BR-1 promotes apoptosis by inactivation of the JAK/STAT5 and PI3K/AKT pathways, while inhibits cell proliferation through arresting cell cycle in the S phase. In addition, a combination of BR-1 with sorafenib can further improve the therapeutic effect on AML. Thus, our results demonstrated that BR-1 would be a novel and potent therapeutic agent to AML, and its combination with other anti-AML drugs would be a promising strategy for AML therapy.

Clinical characteristics and outcomes of Castleman disease: A multicenter study of 185 Chinese patients.

Castleman disease (CD) is a rare lymphoproliferative disorder. To assess the clinical features, outcomes, and prognostic factors of this disease, we retrospectively analyzed 185 HIV-negative CD patients from four medical centers in southern China. The median age was 37 years. One hundred and twenty-one patients (65.4%) were classified as unicentric CD (UCD) and 64 patients (34.6%) were classified as multicentric CD (MCD). The histology subtype was hyaline-vascular for 132 patients (71.4%), plasma cell for 50 patients (27%), and mixed type for 3 patients (1.6%). The 5-year overall survival (OS) of 185 CD cases was 80.3%. All UCD patients underwent surgical excision, whereas the treatment strategies of MCD patients were heterogeneous. The outcome for UCD patients was better than MCD patients, with 5-year OS rates of 93.6% and 51.2%, respectively. In further analysis of the MCD subgroup, a multivariate analysis using a Cox regression model revealed that age, splenomegaly and pretreatment serum albumin level were independent prognostic factors for OS. This multicenter study comprising the largest sample size to date suggested that MCD is a distinct entity from UCD with a significantly worse outcome. Older age (≥40 years), splenomegaly, and hypoalbuminemia were risk factors for poorer MCD prognosis.

Investigation of the optimal duration of bed rest in the supine position to reduce complications after lumbar puncture combined with intrathecal chemotherapy: a multicenter prospective randomized controlled trial.

PURPOSE: This randomized, open-label trial was conducted to investigate the optimal duration of bed rest after intrathecal chemotherapy to reduce the incidence of complications without increasing patients' tolerance to long-term bed rest. METHODS: A total of 390 patients receiving intrathecal chemotherapy were randomly assigned 1:1:1 to undergo bed rest for 6, 8, or 10 h after intrathecal chemotherapy. The primary outcome was the rate of complications after intrathecal chemotherapy. The analysis was per protocol. RESULTS: A total of 359 patients among the 390 patients in our study completed follow-up with 120 patients in the 6-h group, 120 in the 8-h group, and 119 in the 10-h group. The complications among the three groups differed significantly (P = 0.005). The 6-h group had significantly more complications than the 8- (50, 41.7% vs 29, 24.2%, P = 0.004) and 10-h groups (50, 41.7% vs 31, 26.1%, P = 0.011), whereas the difference between the 8- and 10-h groups was not significant (29, 24.2% vs 31, 26.1%, P = 0.737). CONCLUSIONS: The overall results support that the optimal time interval for bed rest in the supine position after intrathecal chemotherapy is 8 h. This trial is registered with the Chinese Clinical Trial Registry (number ChiCTR-IOR-17011671).

Targeting GLI1 Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells.

BACKGROUND/AIMS: Resistance of leukemia stem cells (LSCs) to chemotherapy in patients with acute myeloid leukemia (AML) causes relapse of disease. Hedgehog (Hh) signaling plays a critical role in the maintenance and differentiation of cancer stem cells. Yet its role in AML remains controversial. The purpose of the present study is to investigate the role of GLI1, the transcriptional activator of Hh signaling, in AML progenitor cells and to explore the anti-AML effects of GLI small-molecule inhibitor GANT61. METHODS: The expression of GLI1 mRNA and protein were examined in AML progenitor cells and normal cells. The proliferation, colony formation, apoptosis and differentiation of AML progenitor cells were also analyzed in the presence of GANT61. RESULTS: Kasumi-1 and KG1a cells, containing more CD34+ cells, expressed higher level of GLI1 compared to U937 and NB4 cells with fewer CD34+ cells. Consistently, a positive correlation between the protein levels of GLI1 and CD34 was validated in the bone marrow mononuclear cells (BMMC) of AML patients tested. GANT61 inhibited the proliferation and colony formation in AML cell lines. Importantly, GANT61 induced apoptosis in CD34+ enriched Kasumi-1 and KG1a cells, whereas it induced differentiation in U937 and NB4 cells. Furthermore, GANT61 enhanced the cytotoxicity of cytarabine (Ara-c) in primary CD34+ AML cells, indicating that inhibition of GLI1 could be a promising strategy to enhance chemosensitivity. CONCLUSIONS: The present findings suggested that Hh signaling was activated in AML progenitor cells. GLI1 acted as a potential target for AML therapy.

Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD-negative acute myeloid leukemia.

BACKGROUND: Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD-negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD-negative AML. METHODS: A total of 112 FLT3-ITD-negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD-negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3. RESULTS: Compared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD-negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3's oncogenic role in leukemogenesis. CONCLUSIONS: Our results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD-positive and FLT3-ITD-negative AML and could be a potential therapeutic target.

Role of Measurable Residual Disease in Older Adult Acute Myeloid Leukemia.

There is overwhelming evidence indicating that the use of measurable residual disease (MRD) as a biomarker provides critical prognostic information and that MRD may have a role in directing postremission decisions. There are a variety of assays for MRD assessment, such as multiparameter flow cytometry and molecular assessment of MRD, which present different characteristics in patients older than 60 years of age. Due to multiple reasons related to age, the progress of older adult AML patients is rarely investigated, especially with respect to MRD. In this review, we will clarify the characteristics of different assays for assessing MRD, focusing on its role as a risk-stratification biomarker to predict prognostic information and its role in optimal postremission therapy among older adult AML patients. These characteristics also provide guidance regarding the potential to apply personalized medicine in older adult AML patients.

Histone methylation modification patterns and relevant M-RiskScore in acute myeloid leukemia.

Objective: We tried to identify novel molecular subtypes of acute myeloid leukemia (AML) associated with histone methylation and established a relevant scoring system to predict treatment response and prognosis of AML. Methods: Gene expression data and clinical characteristics of patients with AML were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Molecular subtyping was carried out by consensus clustering analysis, based on the expression of 24 histone methylation modification regulators (HMMRs). The clinical and biological features of each clustered pattern were taken into account. The scoring system was constructed by using differential expression analysis, Cox regression method and lasso regression analysis. Subsequently, the scoring system in the roles of prognostic and chemotherapeutic prediction of AML were explored. Finally, an independent GSE dataset was used for validating the established clustering system. Results: Two distinct subtypes of AML were identified based on the expression of the 24 HMMRs, which exhibited remarkable differences in several clinical and biological characteristics, including HMMRs expression, AML-M0 distribution, NPM1 mutation, tumor mutation burden, somatic mutations, pathway activation, immune cell infiltration and patient survival. The scoring system, M-RiskScore, was established. Integrated analysis demonstrated that patients with the low M-RiskScore displayed a prominent survival advantage and a good response to decitabine treatment, while patients with high M-RiskScore have resistance to decitabine, but they could benefit from IA regimen therapy. Conclusion: Detection of HMMRs expression would be a potential strategy for AML subtyping. Meanwhile, targeting histone methylation would be a preferred strategy for either AML-M0 or NPM1 mutant patients. M-RiskScore was a useful prognostic biomarker and a guide for the choice of appropriate chemotherapy strategy.

Decitabine Enhances Acute Myeloid Leukemia Cell Apoptosis through SH3BGRL Upregulation.

BACKGROUND: SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is downregulated in acute myeloid leukemia (AML). Clinically, DNA demethylating drug decitabine (DAC) combined with traditional chemotherapies reveals better efficacy on AML patients than the conventional chemotherapies alone. Our previous results revealed that human SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) plays a tumor suppressive role in AML but whether there is a connection between DAC and SH3BGRL expression remains elusive. METHODS: Here, we tentatively treated AML cell lines U937, MV4, and HL-60 with DAC and Western Blots, RT-PCR was used to detect the expression of SH3BGRL. Cell proliferation and apoptosis were determined using Annexin V/7- AAD staining. Real-time RT-PCR and Western blot were used to determine the expression of SH3BGRL mRNA and protein. Methylation-specific PCR was used to quantify the DNA methylation in AML cell lines. RESULTS: DAC had cytotoxicity in HL-60, MV4, and U937. In U937 cell lines, treatment with DAC showed the upregulation of cleaved caspase3, PARP, and SH3BGRL. Upon treatment, up-regulation of SH3BGRL mRNA and protein was dose-dependent and this activity was partially inhibited in endogenous SH3BGRL knockdown cell lines. CONCLUSION: Thus, our results demonstrated a possibly cytotoxic role of DAC on AML cells by upregulation of SH3BGRL expression at epigenetic modulation level and the methylation status in the SH3BGRL promoter region could be a supplemental diagnostic marker to the precise administration of DAC to AML patients.

A favorable inductive remission rate for decitabine combined with chemotherapy as a first course in <60-year-old acute myeloid leukemia patients with myelodysplasia syndrome features.

In acute myeloid leukemia (AML), myelodysplasia-related changes contribute to a poor prognosis. This retrospective, propensity score-matched study analyzed 108 newly diagnosed AML patients with features of myelodysplasia syndrome (MDS) (aged 14-60 years) from 2014 to 2018, who received either idarubicin and cytarabine (IA) or decitabine, idarubicin and cytarabine (DAC+IA), and compared efficacy and toxicity between the two regimens. After propensity score matching, there were 54 patients in each group. The rate of complete remission (CR) was higher in the DAC+IA group than in the IA group (85.2% vs 68.5%, P = .040) after the first course, and toxicities were comparable in both groups. Multivariate analysis indicated that the combination with DAC was independent factor for CR rate after the first induction therapy (OR = 2.978, 95% CI:1.090-8.137, P = .033). Subgroup analysis showed a CR advantage for DAC+IA (vs IA) for patients of intermediate-high risk status according to National Comprehensive Cancer Network prognostic stratification. In conclusion, DAC+IA is therefore offered as a new induction choice for newly diagnosed AML patients with features of MDS, aged <60 years old, especially in intermediate-high risk status.

[The clinical features, chemotherapy responses and survival of 223 patients with newly diagnosed multiple myeloma].

OBJECTIVE: To explore the proportion, clinical and laboratory features, chemotherapy responses and long term survival of different kinds of newly diagnosed multiple myeloma (MM) in China. METHODS: The clinical data of 223 cases of newly diagnosed MM patients were gathered in the First Affiliated Hospital of Sun Yat-sen University from Jan, 2000 to Seb, 2007 were retrospectively analyzed. RESULTS: The proportions of each kind of MM including IgG, IgA, light chain, IgD, IgM and biclonal MM were 48.0%, 20.6%, 25.6%, 4.0%, 0.9% and 0.9% respectively. No IgE and nonsecretory myeloma was found. The median age of onset was 58 years, of which that of the IgA type was the oldest one and the light chain type was the youngest (P = 0.004). Bone pain, renal insufficiency, and anemia were the most common symptoms which accounted for 67.7%, 61.0% and 45.3% respectively. The incidences of renal inadequacy, hypercalcemia and pathological fracture in light chain type were higher than those in IgG and IgA types. Besides, no M protein were found in serum protein electrophoresis and no elevation of total globulin. The clinical features of IgD type were similar to that of the light-chain type. The total chemotherapy efficacy rate of 89 patients who were treated with more than 3 cycles in our hospital is 61.8%, which has no difference in all types. Median overall survival of the 89 patients was 33.0 months. CONCLUSION: IgG is the most common type in MM. Bone pain, anemia, hypercalcemia and renal insufficiency are common symptoms. Immunofixation electrophoresis should be performed routinely to avoid missed diagnosis of light-chain and IgD types of MM.

Retraction Note: Downregulated poly-C binding protein-1 is a novel predictor associated with poor prognosis in acute myeloid leukemia.

This article [1] is retracted at request of the Editor.

Value of systemic PET/CT in the diagnosis and differential diagnosis of aplastic anemia.

The aim of the present study was to investigate the value of systemic [18F]fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in the diagnosis and differential diagnosis of aplastic anemia (AA). Systemic PET/CT imaging results of 24 patients diagnosed with AA in The First Affiliated Hospital of Sun Yat-Sen University between May 2011 and August 2014 were retrospectively analyzed and compared with results from healthy individuals and patients with acute leukemia (AL) or myelodysplastic syndrome (MDS) in the same period to summarize the PET/CT characteristics of patients with AA. Systemic PET/CT manifestations of the 24 patients with AA were classified into three types: Normal bone marrow metabolism, hypometabolism and hypometabolism complicated by focal hyperproliferation. Focal hyperproliferation was frequently identified in the vertebral body, breast bones and iliac bones. Bone marrow maximum standardized uptake values (SUV) of AA were associated, to certain extents, with the degree of proliferation and the bone marrow T/B cell ratio. The overall bone marrow SUV of AA were lower compared with those of healthy individuals and AL or patients with MDS, indicating hypometabolism. Considering the T/B cell ratio, systemic PET/CT manifestations of patients with AA are able to predict treatment responses to certain degrees. Systemic PET/CT is highly valuable in the diagnosis and differential diagnosis of AA, and may also indicate treatment responses.

SH3BGRL as a novel prognostic biomarker is down-regulated in acute myeloid leukemia.

Phosphatase PRL-3 expression is positively associated to acute myeloid leukemia (AML) progression and drug resistance. SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL), a downstream effector of PRL-3, plays a tumor suppressive role in solid tumors, but it remains elusive in AML. Here, we followed up and validated the relevance of SH3BGRL expression to AML progression in 116 cases. Results showed that SH3BGRL is down-regulated in 62.37% AML cases with poor prognosis. Cases with positive response to therapy accompanies with SH3GRL expression restoration. Mechanistically, SH3BGRL down-regulation promotes AML cell cycle progression and enhances the anti-apoptotic ability to drug cytotoxicity. While ectopic SH3BGRL blocks AML cell cycle and proliferation to sensitize them to therapeutic drugs via apoptosis. Xenograft assays further confirmed the suppressive role of SH3BGRL in leukemogenesis. Thus, our results demonstrated that SH3BGRL is a novel crucial player in AML progression and could be both a potential diagnostic and prognostic marker.

[Effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia].

OBJECTIVE: To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML). METHODS: Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase. Allo-HSCT from HLA identical siblings was performed for 35 patients, of whom 11 received bone marrow transplantation (BMT) and 24 peripheral blood stem cell transplantation (PBSCT). Conditioning regimens was TBI (total-body irradiation) + CY (CTX) protocol in 8 patients and BU/CY protocol in 27 patients. The average follow-up was 48 months (range 7 - 108 months). RESULTS: 34 (97.1%) patients were successfully engrafted. Among them, 21 patients (60.0%) had three years disease-free (DFS) survival. The overall 5-year survival (OS) was 57.1%. Two patients (5.7%) relapsed. Transplant-related mortality occurred in 12 patients. Hemorrhagic cystitis (HC) occurred in 5 patients and HVOD was observed in 1 patient. Acute graft-versus-host disease (aGVHD) occurred in 18 patients (51.4%), among them 7 patients (20.0%) were of grade III-IV. Chronic GVHD was in 17 patients (48.5%). There was no significant difference in 3-years DFS between BMT group and PBSCT group (54.5% vs. 62.5%, P > 0.05). The 3-year disease-free survival (DFS) was 42.9% in TBI/CY group and 55.6% in BU/CY group (P > 0.05). In univariate prognostic analysis model, the DFS at 3 years is 75% and 47.4% for < or =30 years patients and >30 years patients, respectively, P < 0.05. The 3-year DFS of patients with first chronic phase is higher than patients with advanced diseases (61.3% vs. 40%, P < 0. 05). The 3-year DFS in patients of grade I - II GVHD was higher than that in patients of grade III-IV GVHD (81.8% vs. 14.3%, P < 0.05). CONCLUSION: The patients who had transplantation done within 1 year after diagnosis during their first chronic phase of disease and who had low-grade GVHD have better prognosis. Those patients who had III-IV acute GVHD are prone to incorporate severe infection, which was a worse prognostic factor of allo-HSCT for chronic myelogenous leukemia.

Downregulated Poly-C binding protein-1 is a novel predictor associated with poor prognosis in Acute Myeloid Leukemia.

BACKGROUND: Depletion of Poly-C binding protein-1(PCBP1) is implicated in various human malignancies. However, the underlying biological effect of PCBP1 in cancers, including acute myeloid leukemia (AML), still remains elusive. The purpose of this study was to examine the expression and clinical outcome of PCBP1in acute myeloid leukemia. METHODS: Bone marrow fluids of 88 newly diagnosed AML patients were sampled, and the PCBP1 mRNA expression level was evaluated using quantitative RT-PCR. The association between PCBP1 expression and clinicopathological features or the survival status of the patients was assessed by Chi-square test and Kaplan-Meier method. RESULTS: Comparing newly diagnosed AML patients to normal healthy donors, PCBP1 expression was significantly decreased in AML patients (P < 0.001). Conversely, PCBP1 expression had accordingly recovered back to normal in patients with complete remission (P < 0.001). Clinical feature analyses showed that PCBP1 expression was negatively correlated with white blood cell count (P = 0.024). In addition, patients with low PCBP1 expression had poor disease-free survival (11.8% vs. 45.3%; P = 0.01) and overall survival (18.2% vs. 42.4%; P = 0.032), respectively. CONCLUSIONS: Taken together, our results showed for the first time that expression of PCBP1 was down-regulated in newly diagnosed AML patients and might be an independent prognostic marker in AML and should to be further investigated.

Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells.

P-glycoprotein (P-gp, ABCB1) overexpression and enrichment of stem-like cells are linked to poor prognosis in tumor patients. In this study, we investigated the effect of apatinib, an oral multi-targeted tyrosine kinase inhibitor (TKI) on enhancing the efficacy of conventional anticancer drugs in side population (SP) cells and ABCB1-overexpressing leukemia cells in vitro, in vivo and ex vivo. Our results showed that apatinib significantly enhanced the cytotoxicity and cell apoptosis induced by doxorubicin in SP cells sorted from K562 cells. Furthermore, apatinib also strongly reversed multidrug resistance (MDR) in K562/ADR cells, and the primary leukemia blasts overexpressing ABCB1 while showed no synergistic interactions with chemotherapeutic agents in MRP1-, MRP4-, MRP7- and LRP-overexpressing cells. Apatinib treatment markedly increased the intracellular accumulation of doxorubicin and rhodamine 123 in K562/ADR cells and the accumulation of rhodamine 123 in the primary leukemia blasts with ABCB1 overexpression. Apatinib stimulated the ATPase activity of P-gp in a dose-dependent manner but did not alter the expression of ABCB1 at both mRNA and protein levels. The phosphorylation level of AKT and ERK1/2 remained unchanged after apatinib treatment in both sensitive and MDR cells. Importantly, apatinib significantly enhanced the antitumor activity of doxorubicin in nude mice bearing K562/ADR xenografts. Taken together, our results suggest that apatinib could target to SP cells and ABCB1-overexpressing leukemia cells to enhance the efficacy of chemotherapeutic drugs. These findings should be useful for the combination of apatinib and chemotherapeutic agents in the clinic.

[Inhibitory effect of apatinib on HL-60 cell proliferation and its mechanism].

OBJECTIVE: To investigate the effect of apatinib, a small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, on the proliferation of human acute myeloid leukemia HL-60 cells and explore the possible mechanism. METHODS: MTT assay was used to assess the cytotoxicity of apatinib in HL-60 cells. The apoptosis and cell cycle changes of the cells in response to apatinib treatment were analyzed by flow cytometry, and Western blotting was used to assay P-Akt and P-Erk1/2 expressions in the cells. RESULTS: Apatinib significantly inhibited the proliferation of HL-60 cells in vitro with an IC(50) of 4.96∓0.32 µmol/L. Apatinib treatment significantly increased the apoptotic rate of the cells in a dose-dependent manner, but produced no significant effect on the cell cycle (P>0.05). Western blotting showed that the expressions of P-Akt and P-Erk1/2 decreased in HL-60 cells after a 48-h apatinib treatment. CONCLUSION: Apatinib inhibits the proliferation of HL-60 cells by inducing cell apoptosis probably through the mechanism of inhibiting the expressions of the Akt/Erk1/2 signal transduction pathway.

Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia.

BACKGROUND: Functional polymorphisms of the ABCG2 gene may contribute to individual variability in drug response and the prognosis of patients. METHODS: In the present study, the genetic polymorphisms and expression of ABCG2 were analysed in blasts cells obtained from 184 Chinese patients with de novo acute leukaemia to investigate their possible association with clinical outcomes. RESULTS: A novel synonymous ABCG2-single nucleotide polymorphism (SNP) at exon 16 (13561218 C/T) and five known SNPs at exon 2 (13608835 G/A), exon 5 (13600044 C/A), intron 10 (13576005 C/T), intron 13 (13564503 C/T) and intron 14 (13563578 A/G) were identified with occurrence rates of 1.1%, 64.1%, 30.4%, 21.2%, 39.7% and 28.8%, respectively. We found that patients with the ABCG2 34GG genotype displayed longer disease free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with the 34GA/AA genotypes. Furthermore, the DFS and OS were significantly diminished in bone marrow transplantation (BMT) patients with the 34GA/AA genotypes relative to those with the 34GG genotype. CONCLUSIONS: These results suggest that these highly prevalent ABCG2 34GA/AA genotypes are associated with poor prognosis of Chinese patients with acute leukaemia and BMT patients.

Up-regulation of ABCB1/P-glycoprotein by escaping promoter hypermethylation indicates poor prognosis in hematologic malignancy patients with and without bone marrow transplantation.

We investigated the correlation between MDR1 promoter methylation status and MDR1 expression in 228 hematologic malignancies patients and 90 healthy controls. High level of MDR1 mRNA correlated to promoter hypomethylation and strongly associated with poor prognosis indicated by 2-year survival rates, poor CR rate (without BMT) and high relapse rate (with BMT). Furthermore, relative luciferase activity of methylated MDR1 at promoter -50 region was significantly higher than that of the unmethylated. In addition, MDR1 in K562 cells elevated significantly after 5-Aza-dC treatment. In summary, MDR1 promoter hypomethylation conferred its up-regulation and indicated poor prognosis in patients with and without BMT.