Clonal Evolution: Driver/Passenger Mutation Model in CLL

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

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Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

Scientific Reports ◽

10.1038/s41598-021-95109-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shumaila Sayyab ◽

Anders Lundmark ◽

Malin Larsson ◽

Markus Ringnér ◽

Sara Nystedt ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Large Scale ◽

Somatic Mutations ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Point Mutations ◽

Driver Genes ◽

Protein Coding ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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Next-generation sequencing reveals gene mutations landscape and clonal evolution in patients with acute myeloid leukemia

Hematology ◽

10.1080/16078454.2020.1858610 ◽

2021 ◽

Vol 26 (1) ◽

pp. 111-122

Author(s):

Xiao Chen ◽

Han Zhu ◽

Chun Qiao ◽

Sishu Zhao ◽

Lu Liu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Next Generation Sequencing ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Gene Mutations ◽

Next Generation ◽

Generation Sequencing ◽

Acute Myeloid

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An evaluation of genetic distances for use with microsatellite loci.

Genetics ◽

10.1093/genetics/139.1.463 ◽

1995 ◽

Vol 139 (1) ◽

pp. 463-471 ◽

Cited By ~ 22

Author(s):

D B Goldstein ◽

A Ruiz Linares ◽

L L Cavalli-Sforza ◽

M W Feldman

Keyword(s):

Microsatellite Loci ◽

Phylogenetic Reconstruction ◽

Genetic Distances ◽

Stepwise Mutation Model ◽

Mutation Model ◽

Stepwise Mutation ◽

The Difference ◽

Nei's Distance ◽

Infinite Alleles Model ◽

Overall Reliability

Abstract Mutations of alleles at microsatellite loci tend to result in alleles with repeat scores similar to those of the alleles from which they were derived. Therefore the difference in repeat score between alleles carries information about the amount of time that has passed since they shared a common ancestral allele. This information is ignored by genetic distances based on the infinite alleles model. Here we develop a genetic distance based on the stepwise mutation model that includes allelic repeat score. We adapt earlier treatments of the stepwise mutation model to show analytically that the expectation of this distance is a linear function of time. We then use computer simulations to evaluate the overall reliability of this distance and to compare it with allele sharing and Nei's distance. We find that no distance is uniformly superior for all purposes, but that for phylogenetic reconstruction of taxa that are sufficiently diverged, our new distance is preferable.

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Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽

10.3390/cancers13133296 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3296

Author(s):

Ioannis Chanias ◽

Kristina Stojkov ◽

Gregor Stehle ◽

Michael Daskalakis ◽

Helena Simeunovic ◽

...

Keyword(s):

Precision Medicine ◽

Myelodysplastic Syndromes ◽

Clonal Evolution ◽

Driver Mutations ◽

Future Perspectives ◽

Hematopoietic Stem ◽

Secondary Acute Myeloid Leukemia ◽

Stem And Progenitor Cells ◽

Unfit Patients ◽

Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

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EnvIRONmental Aspects in Myelodysplastic Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22105202 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5202

Author(s):

Verena Petzer ◽

Igor Theurl ◽

Günter Weiss ◽

Dominik Wolf

Keyword(s):

Myelodysplastic Syndrome ◽

Iron Overload ◽

Iron Homeostasis ◽

Clonal Evolution ◽

Red Blood Cell Transfusion ◽

Bone Marrow Niche ◽

Environmental Aspects ◽

Complete Understanding ◽

Mediated Effects ◽

Important Player

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.

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