Icy moons' geysers: from laboratory to theory

Stars and planetary system

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models

Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signalin

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo

Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression

Purpose: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. Methods: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. Results: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. Conclusion: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models. Copyright © 2020 American Society of Clinical Oncology

Progression risk stratification of asymptomatic Waldenström macroglobulinemia

BACKGROUND Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, b2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application (www.awmrisk.com). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention. © 2019 by American Society of Clinical Oncolog

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients