Biomedical subjects

Rhonda E Ries

Publications and source records attributed to Rhonda E Ries.

5 recordsLinked to original sources

PubMed2026

Prognostic impact of age and MDS-associated mutations in NPM1-mutated AML.

Nucleophosmin-1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML) and is generally associated with favorable prognosis. However, the impact of myelodysplastic syndrome-associated mutations (MDSm+) on patient outcomes within this subgroup remains uncertain. We retrospectively analyzed 271 patients with NPM1-mutated AML from 3 independent cohorts (SWOG, Fred Hutch, and Beat AML) to assess the prognostic significance of MDSm+ and its interaction with age. MDSm+ occurred in 17% of patients, most commonly involving SRSF2 and SF3B1. Although MDSm+ was associated with inferior overall survival (OS) compared with MDSm- in European LeukemiaNet (ELN) 2022 favorable-risk patients (hazard ratio [HR], 2.0; P = .008), this effect was largely driven by worse outcomes in older patients (≥65 years) as older ELN2022 favorable-risk patients had poor OS regardless of the presence of MDSm+ compared with younger patients. After stratification of patients by age, there was not a significant difference between MDSm+ and MDSm- in either younger patients (HR, 0.99; P = .98) or older patients (HR, 1.42; P = .33). These findings indicate that MDSm+ in NPM1 + AML is not independently associated with adverse risk after adjusting for age, and highlight the need for age-adjusted AML risk models.

Journal Article↗

PubMed2025

EZH2-driven immune evasion at disease presentation defines a targetable high-risk subset of acute leukemia exemplified by t(16;21) FUS::ERG AML.

The past 25 years of clinical trials have produced few improvements in pediatric AML (pAML) outcomes. This is acutely evident in patients with t(16;21)(p11;q22), yielding FUS::ERG. Patients with FUS::ERG-positive AML relapse quickly and do not respond to transplantation. Major histocompatibility complex (MHC) class I & II receptors and costimulatory molecules are absent at diagnosis in FUS::ERG-positive AML, mirroring the phenotype and outcomes of post-transplant relapse. We show that this is driven by overexpression of EZH2, in vitro and in multiple clinical cohorts. While FUS::ERG AML is the most extreme example, this phenotype is shared by lethal CBFA2T3::GLIS2-driven AML, and patients with RUNX1::RUNX1T1 have significantly worse outcomes when EZH2 overexpression co-occurs. The FDA-approved EZH2 inhibitor tazemetostat reverses this phenotype, re-establishes MHC presentation, and elicits immune effector cell-mediated elimination. EZH2 inhibitors may provide the first targeted therapeutic frontline option for AML patients with FUS::ERG, with the potential for broader frontline immunostimulatory benefits.

Journal Article↗

PubMed2006

Expression of a bcr-1 isoform of RARalpha-PML does not affect the penetrance of acute promyelocytic leukemia or the acquisition of an interstitial deletion on mouse chromosome 2.

Expression of a bcr-3 isoform of retinoic acid receptor alpha-promyelocytic leukemia (RARalpha-PML) in mice expressing a bcr-1 isoform of PML-RARalpha is associated with increased penetrance of murine acute promyelocytic leukemia (APL) and the frequent acquisition of an interstitial deletion of one copy of mouse chromosome 2 (del(2)). To determine whether the isoform of RARalpha-PML is important for these effects, we created mice that expressed a bcr-1 isoform of RARalpha-PML. Coexpression with the bcr-1 isoform of PML-RARalpha did not increase the penetrance of APL (7 of 45 animals developed APL with PML-RARalpha alone vs 12 of 44 with both transgenes; P=.19). Furthermore, the frequency of del(2) in APL cells from doubly transgenic mice was not different from that of mice expressing PML-RARalpha alone (3 of 6 vs 6 of 12, respectively-P=1.38-compared with 11 of 11 for mice coexpressing PML-RARalpha and bcr-3 RARalpha-PML). The bcr-1 and bcr-3 isoforms of RARalpha-PML, therefore, have different biological activities that may be relevant for the pathogenesis of murine APL.

Animals↗

PubMed2005

Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha.

PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARalpha (PR) and RARalpha-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1. To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1+/- mice and assessed their phenotype. Young, nonleukemic hCG-PR x PU.1+/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR x PU.1+/- mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR x PU.1+/+ mice (P < 0.0001). The residual PU.1 allele in hCG-PR x PU.1+/- APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL.

Animals↗

PubMed2003

A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes.

In this pilot study, we used primary human acute myeloid leukemia (AML) cell genomes as templates for exonic PCR amplification, followed by high-throughput resequencing, analyzing approximately 7 million base pairs of DNA from 140 AML samples and 48 controls. We identified six previously described, and seven previously undescribed sequence changes that may be relevant for AML pathogenesis. Because the sequencing templates were generated from primary AML cells, the technique favors the detection of mutations from the most dominant clones within the tumor cell mixture. This strategy represents a viable approach for the detection of potentially relevant, nonrandom mutations in primary human cancer cell genomes.

Case-Control Studies↗