Biology subjects

Welch, J. S.

Publications and source records attributed to Welch, J. S..

3 recordsLinked to original sources

bioRxiv2021

Immunosuppression and Outcomes in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) patients rarely have long first remissions (> 5 years) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, short remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing and functional immunologic studies, we characterized 28 Normal Karyotype (NK)-AML patients with >5 year first remissions after chemotherapy (Long First Remissions, LFR) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 years (Standard First Remissions, SFR). Our combined analyses indicated that genetic risk profiling at presentation (as defined by ELN 2017 Criteria) was not sufficient to explain the outcomes of many SFR cases. Single cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T-cells expressed an exhaustion signature and were resistant to activation by T-cell receptor stimulation in the presence of autologous AML cells. T-cell activation could be restored by removing the AML cells, or blocking the inhibitory MHC Class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T-cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

cancer biology↗

bioRxiv2021

Bexarotene derivatives modify responses in acute myeloid leukemia

The retinoids all-trans retinoic acid (ATRA) and bexarotene are active in acute myeloid leukemia (AML), but responses beyond acute promyelocytic leukemia (APL) have been more modest than APL responses. To determine whether chemical modification of bexarotene might augment retinoid responses in AML, we screened a series of 38 bexarotene derivatives for activity in a mouse MLL-AF9 leukemia cell line, which exhibits strong synergistic sensitivity to the combination of ATRA and bexarotene. We found that RXRA potency correlated with anti-leukemic activity and that only one compound (103-4) with dual RARA/RXRA activity was capable of ATRA-independent anti-leukemic activity. We evaluated bioisostere and cyclohexane modifications for potential resistance to P450 metabolism and found that bioisosteres reduced potency and that bezopyran, cyclopentane, and cyclohexene modifications only modestly reduced susceptibility to metabolism. Collectively, these studies provide a map of the structure-activity relationships of bexarotene with outcomes related to RXRA and RARA activity, corepressor binding, compound stability, and anti-leukemic potential.

cancer biology↗

bioRxiv2021

Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples

Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4,000 focal regions that were uniquely hypermethylated vs. normal CD34+ cells. These regions had modest, but significant, hypermethylation in AMLs with biallelic TET2 mutations, and 5-hydroxymethylation levels that were dependent on functional TET2, indicating that hypermethylation in these regions is caused by inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred in regions with low methylation in normal CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that methylation in these regions is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.

cancer biology↗