Chunlin Zhou

TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia.

The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARα fusion gene. Although the PML-RARα fusion gene can be detected in >98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARα is the 10th RARα chimeric gene that has been reported up to now. TBLR1-RARα contained the B-F domains of RARα and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor α. As a result, TBLR1-RARα exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARα. In the presence of pharmacologic doses of ATRA, TBLR1-RARα could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARα target genes, and cell differentiation induction in a dose- and time-dependent manner.

Some novel features of IDH1-mutated acute myeloid leukemia revealed in Chinese patients.

Mutations of isocitrate dehydrogenase 1 (IDH1) have recently been reported in acute myeloid leukemia (AML). However, the characteristics of IDH1-mutated AML are still not known clearly. We analyzed 416 Chinese AML patients and found 28 patients (6.7%) carried this mutation. One homozygous IDH1 mutant in AML was found. The IDH1 mutations were associated with NPM1 mutations (P=0.043) and could coexist with recurrent transcription factor aberrations including AML1-ETO (6/50), PML-RARα (3/77) and CBFβ-MYH11 (1/15). For AML with AML1-ETO fusion gene, IDH1(mut) patients may have worse disease-free survival (DFS) than IDH1(wild-type) patients.

Clinical and laboratory studies of 17 patients with acute myeloid leukemia harboring t(7;11)(p15;p15) translocation

The cellular and molecular genetic aberrations of hematopoietic and lymphoid tissues are increasingly important in leukemia classification and are prognostically significant. Although some recurrent molecular cytogenetic abnormalities in AML have been extensively studied, others including t(7;11)(p15;p15) have not been well characterized. In this paper, seventeen AML patients with t(7;11)(p15;p15) were retrospectively reviewed for cell morphology, immuno-phenotype, cytogenetics as well as clinical features and prognosis. Among them, thirteen were female; nine were AML-M2. Six patients who were newly diagnosed were alive, one was lost for followed up and ten died. The median survival was 8 months. Taking together, AML with t(7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis.

Risk factors of long-term incidences of thrombosis, myelofibrosis and evolution into malignance in polycythemia vera: a single center experience from China

To find out risk factors of incidences of long-term complications of thrombosis, myelofibrosis with myeloid metaplasia (MMM) and evolution into malignance in Chinese PV patients, we evaluated 320 PV patients referred to our center from April 1984 to June 2005 by Kaplan–Meier estimation and Cox proportional hazards models. A total of 250 events of thrombosis were observed in 138 (43.13%) patients. Advanced age, prior thrombosis and hemoglobin out of control were statistically significant risk factors of incidences of thrombotic events. A total of 43 patients progressed into MMM at a median time of 84 (7–240) months, higher white blood cell (WBC) count, splenomegaly, receiving alkylating agent and hydroxycarbamide were associated with the progression into MMM. During the follow-up time, 11 and 2 patients died of fatal complications of thrombosis and acute myeloid leukaemia (AML), respectively. These results suggest that advanced age, prior thrombosis and hemoglobin out of control contributed to relatively high incidence of thromboembolism; higher WBC count, splenomegaly, receiving alkylating agent and hydroxycarbamide were risk factors of evolution to MMM. The main poor factors that influenced the survival of Chinese PV patients were incidences of thromboembolism and evolution into AML.

Monitoring of WT1 and its target gene IRF8 expression in acute myeloid leukemia and their significance

Sir, Wilm’s tumor gene 1(WT1) is considered to be a tumor marker expressed in many cancer types. Approximately 90% of acute myeloid leukemia (AML) patients had defective or abnormal WT1 expression, suggesting its involvement in tumor occurrence [1]. The protein products of the WT1 have been shown to directly bind to the interferon regulatory factor 8 (IRF8) promoter and suppress its activity, demonstrating that IRF8 can be regulated by WT1 [2]. Bansal et al. [3] reported that WT1 expression was decreased in the KG-1 cell line after IFNa and IFN-b treatment, providing a potentially new strategy for the treatment of AML. We analyzed the expression levels of WT1 and IRF8 in AML patients and determined the correlation between these two genes with AML outcome. We also evaluated the feasibility of using the expression of these genes as prognostic factors and markers of minimal residual disease in AML. Bone marrow samples from 9 normal donors and 138 patients with de novo AML were collected at the Institute of Hematology and Blood Disease Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College hospital (Clinical data listed in Table S1). The chemotherapy strategy has been reported previously [4, 5]. Mononuclear cells were separated, mRNA was extracted, and reverse transcription were used to prepare cDNA for further evaluation. Gene expression was detected by RT-PCR method (Taqman Probes) with the following primers: WT1: forward 50-CGCTA TTCGC AATCA GGGTT A-30, reverse 50-GGGCG TGTGA CCGTA GCT-30, probe: 50-FAM-AGCAC GGTCA CCTTC GACG GGA-TAMRA-30, product length: 67 bp (the primers detect all four isoforms of WT1); IRF8: forward 50-GAGAG CTGCA GCAGT TCTAT AACA-30, reverse 50-CTGTA TGTCC GGCAA CTGGC-30, probe: 50-CCAAA CTCAT TCTCG TGCAG ATTGA GCA G-30, product length: 148 bp; ABL: forward 50-TGGAG ATAAC ACTCT AAGCA TAACT AAAGG T-30, reverse 50-TGGGT CCCAA GCAAC TACAT C-30, probe: 50-AATGG TGTGA AGCCC AAACC AAAAA TGG-30, product length: 124 bp. Expression levels are presented as the log10 transformation of target gene copy number/10 ABL copy number.

Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.