miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2′-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study.

We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2'-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.

An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models. Mechanistically, the effect was mediated by protein synthesis inhibition and reduction of short-lived proteins, including total and phosphorylated forms of FLT3 and its downstream signaling proteins. A phase 2 clinical trial of sorafenib and HHT combination treatment in FLT3-ITD AML patients resulted in complete remission (true or with insufficient hematological recovery) in 20 of 24 patients (83.3%), reduction of ITD allelic burden, and median leukemia-free and overall survivals of 12 and 33 weeks. The regimen has successfully bridged five patients to allogeneic hematopoietic stem cell transplantation and was well tolerated in patients unfit for conventional chemotherapy, including elderly and heavily pretreated patients. This study validated the principle and clinical relevance of in vitro drug testing and identified an improved treatment for FLT3-ITD AML. The results provided the foundation for phase 2/3 clinical trials to ascertain the clinical efficacy of FLT3 inhibitors and HHT in combination.

To investigate the role of BCL6 in the pathogenesis of gastric lymphoma, we analyzed the BCL6 promoter region for BCL6 translocations, somatic hypermutations, and deregulating mutations in 43 gastric lymphomas, including 4 extranodal marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas), 33 diffuse large Bcell lymphomas (DLBCLs), and 6 composite DLBCLs with residual MALT lymphoma (DLCLMLs). BCL6 promoter substitutions by immunoglobulin (Ig) and non-Ig translocation partners, resulting in its deregulation, were frequently involved in DLBCL (36.4%) and DLCLML (50%). Two novel BCL6 translocation partner genes, 28S rRNA and DMRT1, and a new BCL6 translocation breakpoint in intron 2 were also identified. Deregulating mutations were found only in DLBCL (24.2%), which correlated significantly with high BCL6 protein expression. Significantly, high BCL6 expression correlated strongly with longer overall survival (OS), independent of mechanism in gastric DLBCL and DLCLML. Gastric DLBCLs were further subclassified into germinal center B-cell-like (GCB) and non-GCB subgroups immunohistochemically. High BCL6 expression was detected in all GCB cases, irrespective of BCL6 genetic alterations. In the non-GCB subgroup, BCL6-deregulating mutations correlated significantly with high BCL6 expression level. No significant correlation was found between the BCL6 expression level and OS in the non-GCB subgroup, which had significantly poorer prognosis than the GCB subgroup. IntroductionPrimary gastric lymphoma represents about 80% of all extranodal non-Hodgkin lymphomas (NHLs), and is the most common extranodal NHL in the Hong Kong Chinese population. Based on the World Health Organization (WHO) classification, gastric lymphoma can be further classified into MALT lymphoma (extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue), diffuse large B-cell lymphoma (DLBCL), and composite DLBCL with residual MALT lymphoma (DLCLML; transformed MALT DLBCL). 1 In the West, gastric MALT lymphoma is more prevalent, occurring in up to 75% of patients. 2 However, gastric DLBCL is more frequent in Chinese patients in Hong Kong, accounting for 60% of gastric NHL. 3 MALT lymphomas show histologic features more in common with those of mucosa-associated lymphoid tissue than those of peripheral lymph nodes. They exemplify the close relationship between chronic inflammation and lymphomagenesis, as a strong association has been found between chronic infection with Helicobacter pylori and gastric MALT lymphoma. 4 Specific karyotypic alterations characterize MALT lymphomas: trisomies 3 and 18, and translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32; q21), t(3;14)(q27;q32), and t(3;14)(p14.1;q32). 5 In contrast, gastric DLBCL has a similar histology to its nodal counterpart, but a number of observations suggest that the genetic abnormalities of gastric DLBCL are distinct from those of nodal DLBCL. [6][7][8][9] DLBCL is a heterogeneous entity both clinically and morphologically. Recently, 3 pro...

Introduction This cross-sectional study aimed at evaluating impacts of healthcare simulation training, either in-situ or lab-based, on personal strengths of healthcare workers (HCWs) and organizational outcomes during the COVID-19 pandemic. Methods COVID-19 Taskforce was established to formulate standardized scenario-based simulation training materials in late-January 2020. Post-training questionnaires made up of 5-point Likert scales were distributed to all participants to evaluate their personal strengths, in terms of i) assertiveness, ii) mental preparedness, iii) self-efficacy, iv) internal locus of control, and v) internal locus of responsibility. Independent sample t-tests were used to analyze between-group difference in “In-situ” and “Lab-based” group; and one-sample t-tests were used to compare change in personal strengths with reference point of 3 (Neutral). Kirkpatrick’s Model served as the analytical framework for overall training effects. Results Between 05 February and 18 March 2020, 101 sessions of simulation training were conducted in “In-Situ” at either Accident & Emergency Department (20, 20%) or Intensive Care Unit (15, 14%) and “Lab-based” for Isolation (30, 30%) and General Wards (36, 36%). 1,415 hospital staff members, including 1,167 nurses (82%), 163 doctors (12%) and 85 patient care assistants (6%), were trained. All domains of personal strengths were scored 4.24 or above and statistically significantly increased when comparing with reference population ( p < .001). However, no significant differences between in-situ and lab-based simulation were found ( p > .05), for all domains of personal strengths. Conclusion Healthcare simulation training enhanced healthcare workers’ personal strengths critical to operational and clinical outcomes during the COVID-19 pandemic.

The data independently validate for the first time the significance of the HBS1L-MYB intergenic region in regulating HbF expression in a separate ethnic group that has a high prevalence of beta-thalassaemia. Functional studies to unravel the biological significance of this region in regulating HbF production is clearly indicated, which may lead to new strategies to modify the disease course of severe HBB disorders.

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Our results suggest that As(2)O(3) may be superior to chemotherapy and BMT for the treatment of APL in relapse.