(
) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence ...that
mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring
mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that
mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy in terms of clinical features, underlying pathogenesis and treatment outcomes. Recent advances in genomic techniques have ...unraveled the molecular complexity of AML leukemogenesis, which in turn have led to refinement of risk stratification and personalized therapeutic strategies for patients with AML. Incorporation of prognostic and druggable genetic biomarkers into clinical practice to guide patient-specific treatment is going to be the mainstay in AML therapeutics. Since 2017 there has been an explosion of novel treatment options to tailor personalized therapy for AML patients. In the past 3 years, the U.S. Food and Drug Administration approved a total of eight drugs for the treatment of AML; most specifically target certain gene mutations, biological pathways, or surface antigen. These novel agents are especially beneficial for older patients or those with comorbidities, in whom the treatment choice is limited and the clinical outcome is very poor. How to balance efficacy and toxicity to further improve patient outcome is clinically relevant. In this review article, we give an overview of the most relevant genetic markers in AML with special focus on the therapeutic implications of these aberrations.
Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct ...molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
Limited real-world data are available regarding treatment practices and outcomes of multiple myeloma (MM) in Asia. We conducted a retrospective cohort study using the Taiwan National Healthcare ...Insurance Research database and Taiwan Death Registry and used a Markov model to describe disease progression and outcomes in 4092 patients newly diagnosed with MM from 01-Jan-2007 to 31-Dec-2015. We observed marked differences in the characteristics, length and outcome of the clinical journey between patients who did/did not receive autologous stem cell transplant, and between patients initiated on novel agents versus other treatment regimens. In transplant recipients, initiation with combined thalidomide + bortezomib increased over time (12.2-77.5%). Progression-free survival after first-line treatment improved and a lower percentage of patients died. Lenalidomide in second and third-line regimens increased (15.5-31.5%). In non-transplanted patients, initiation with novel agents increased (17.5-54.6%), but death rates remained high (60.3%). The treatment landscape of MM in Taiwan has evolved, with increased use of combined bortezomib + thalidomide for first-line and lenalidomide for second/third-line but many patients die before receiving second-line treatment. Novel agents with different modes of action should be used as early as possible to maximize their benefits. Improved MM treatments remains a critical medical need.
Summary
Leukaemic stem cell (LSC) gene expression has recently been linked to prognosis in patients with acute myeloid leukaemia (17‐gene LSC score, LSC‐17) and myelodysplastic syndromes. Although ...chronic myelomonocytic leukaemia (CMML) is regarded as a stem cell disorder, the clinical and biological impact of LSCs on CMML patients remains elusive. Making use of multiple independent validation cohorts, we here describe a concise three‐gene expression signature (LSC‐3, derived from the LSC‐17 score) as an independent and robust prognostic factor for leukaemia‐free and overall survival in CMML. We propose that LSC‐3 could be used to supplement existing risk stratification systems, to improve prognostic performance and guide management decisions.
Longer survival in patients with multiple myeloma (MM) after treatment with novel agents (NA) such as thalidomide, bortezomib, and lenalidomide may be associated with increased risks of developing ...second primary malignancies (SPM). Few data describe the risk of SPM in patients with MM in Asia. This population-based retrospective cohort study assessed the risk of SPM in MM using the Taiwan National Cancer Registry and National Health Insurance Research databases from 2000 to 2014. Among 4,327 patients with newly diagnosed MM initiated with either novel agents alone (NA), chemotherapy combined with novel agents (CCNA), or chemotherapy alone (CA), the cumulative incidence of SPM overall was 1.33% at year 3. The SPM incidence per 100 person-years (95% confidence interval CI) was 0.914 (0.745-1.123) overall, 0.762 (0.609-1.766) for solid tumours, and 0.149 (0.090-0.247) for haematological malignancies. We compared risks of SPM using a cause-specific Cox regression model considering death as a competing risk for developing SPM. After controlling for age, gender, Charlson Co-morbidity Index, and time-period, the risk of developing any SPM or any haematological malignancy was significantly reduced in patients initiated on NA (2010-2014 period) compared to chemotherapy alone (adjusted hazard ratio 0.24, 95% CI 0.07-0.85, and 0.10, 95% CI 0.02-0.62, respectively). Contemporary treatment regiments using NA (mainly bortezomib) were associated with a lower risk for a SPM in comparison with CA.
Mutations in CCAAT enhancer binding protein α (CEBPA) occur in approximately 10% of patients with de novo acute myeloid leukemia (AML). Emerging evidence supports that in-frame mutations in the basic ...leucine zipper domain of CEBPA (CEBPA
) confer a survival benefit, and CEBPA
replaced CEBPA double mutations (CEBPA
) as a unique entity in the 2022 World Health Organization (WHO-2022) classification and International Consensus Classification (ICC). However, challenges remain in daily clinical practice since more than 30% patients with CEBPA
die of AML despite intensive treatment. This review aims to provide a comprehensive summary of the heterogeneities observed in AML with CEBPA
and CEBPA
, and will discuss the prognostic implications of concurrent mutations and novel mechanistic targets that may inform future drug development. The ultimate goal is to optimize clinical management and to provide precision medicine for this category of patients.
Summary
Increasing evidence supports the role of the immune microenvironment and associated signalling in the pathogenesis of myelodysplastic syndromes (MDS). Nevertheless, the clinical relevancy of ...immune signals in patients with MDS remains elusive. To address this, we used single‐sample gene‐set enrichment analysis to score immune signatures of bone marrow (BM) samples from 176 patients with primary MDS. Enhanced signatures of ‘immature dendritic cells’ and ‘natural killer cells with cluster of differentiation (CD)56bright’ were correlated with better overall survival (OS), whilst higher ‘CD103+ signature’ was associated with reduced survival. An MDS‐Immune‐Risk (MIR) scoring system was constructed based on the weighted sums derived from Cox regression analysis. High MIR scores were correlated with higher revised International Prognostic Scoring System (IPSS‐R) scores and mutations in ASXL transcriptional regulator 1 (ASXL1), Runt‐related transcription factor 1 (RUNX1), and tumour protein p53 (TP53). High‐score patients had significantly inferior leukaemia‐free survival (LFS) and OS than low‐score patients. The prognostic significance of MIR scores for survival remained valid across IPSS‐R subgroups and was validated in two independent cohorts. Multivariable analysis revealed that a higher MIR score was an independent adverse risk factor for LFS and OS. We further proposed a model with the combination of MIR score and gene mutations to be complementary to IPSS‐R for the prognostication of LFS and OS of patients with MDS.
This study reports the following: (1) frequency of TP53 comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53 mutated ...variant allelic fraction <10%, (3) prognostic impact of -7, -5/del(5q), -17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53.
Aberrant alternative splicing (AS) is involved in leukemogenesis. This study explored the clinical impact of alterations in global AS patterns in 341 patients with acute myeloid leukemia (AML) newly ...diagnosed at the National Taiwan University Hospital and validated it using The Cancer Genome Atlas (TCGA) cohort. While studying normal cord blood CD34+/CD38− cells, we found that AML cells exhibited significantly different global splicing patterns. AML with mutated TP53 had a particularly high degree of genome‐wide aberrations in the splicing patterns. Aberrance in the global splicing pattern was an independent unfavorable prognostic factor affecting the overall survival of patients with AML receiving standard intensive chemotherapy. The integration of global splicing patterns into the 2022 European LeukemiaNet risk classification could stratify AML patients into four groups with distinct prognoses in both our experimental and TCGA cohorts. We further identified four genes with AS alterations that harbored prognostic significance in both of these cohorts. Moreover, these survival‐associated AS events are involved in several important cellular processes that might be associated with poor response to intensive chemotherapy. In summary, our study demonstrated the clinical and biological implications of differential global splicing patterns in AML patients. Further studies with larger prospective cohorts are required to confirm these findings.
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