Histologic transformation (HT) to an aggressive lymphoma is a well-described event in the natural history and clinical course of patients with so-called indolent lymphomas. This phenomenon has been ...studied most extensively in patients with follicular lymphoma and subsequent transformation to a diffuse large B-cell lymphoma, with little literature on HT in nonfollicular lymphomas. Despite a considerable body of information on the pathologic and molecular events associated with HT, its pathogenesis has remained elusive and the molecular information available has not been translated into clinical advances. It remains unclear if there is already a predisposition to HT and whether this can be detected at the time of diagnosis. The rituximab era has been characterized by a significant improvement in the prognosis of patients with B-cell lymphomas, but HT remains one of the most important challenges in the management of patients with indolent lymphoma, the difficulties starting with the diagnosis and definition of HT and ending with the appropriate management and treatment of the event. Going forward, it is crucial to incorporate HT as a major end point in clinical trials and to include patients with HT as subject of such studies if we are to see meaningful progress in the future.
Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an ...approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman's rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rank p < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.
Acute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal ...hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context. To mimic AML infiltration and dissect the cellular crosstalk in human BM, we established humanized ex vivo and in vivo niche models comprising AML cells, normal HSPCs, and mesenchymal stromal cells (MSCs). Both models replicated the suppression of phenotypically defined HSPC differentiation without affecting their viability. As occurs in AML patients, the majority of HSPCs were quiescent and showed enrichment of functional HSCs. HSPC suppression was largely dependent on secreted factors produced by transcriptionally remodeled MSCs. Secretome analysis and functional validation revealed MSC-derived stanniocalcin 1 (STC1) and its transcriptional regulator HIF-1α as limiting factors for HSPC proliferation. Abrogation of either STC1 or HIF-1α alleviated HSPC suppression by AML. This study provides a humanized model to study the crosstalk among HSPCs, leukemia, and their MSC niche, and a molecular mechanism whereby AML impairs normal hematopoiesis by remodeling the mesenchymal niche.
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 ...mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
Key Points
While follicular lymphoma (FL) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (CPC) population. ...Advances in next generation sequencing have provided valuable insights into the genetic landscape of FL and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. Recurrent mutations of histone modifiers KMT2D, CREBBP, EP300, EZH2, ARIDIA, and linker histones are likely early events arising in the CPC pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed FL. This review provides a synopsis of the main epigenetic aberrations and the current efforts in development and testing of epigenetic therapies in this B cell malignancy.
To determine the clinical relevance of Wilms' tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK).
Exons 7 and 9 of WT1 were screened in samples from 470 young ...adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis.
Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio OR = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio HR = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor.
WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.
While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result ...from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.
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