Elevated expression of S100A8 and S100A9 correlates with resistance to the BCL-2 inhibitor venetoclax in AML

Karjalainen, Reijo; Liu, Minxia; Kumar, Ashwini; He, Liye; Malani, Disha; Parsons, Alun; Kontro, Mika; Kallioniemi, Olli; Porkka, Kimmo; Heckman, Caroline A.

doi:10.1038/s41375-019-0504-y

Cited by 27 publications

(23 citation statements)

References 15 publications

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“…S100A8/S100A9 has been associated with glucocorticoid resistance in KMT2A rearranged infant ALL (41). Likewise, expression of S100A8 and S100A9 correlate with resistance to conventional agents and venetoclax in AML (42). Our findings along with previous work indicates that targeting S100A8 is likely to be a promising strategy to restore chemosensitivity.…”

Section: Discussionsupporting

confidence: 73%

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance

et al. 2020

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Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse.Significance: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.

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Section: Discussionsupporting

confidence: 73%

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance

et al. 2020

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“…Upregulation of S100A8 and S100A9 occurs in various human cancer types and may participate in tumor growth, metastasis, angiogenesis and immune evasion Ichikawa et al, 2011;Grebhardt et al, 2014;Goh et al, 2017;Mondet et al, 2021). Elevated expression of S100A8/S100A9 caused glucocorticoid resistance in MLL rearranged infant acute lymphoid leukemia (Spijkers-Hagelstein et al, 2012) and negatively associated with BCL2 inhibitor venetoclax in AML (Karjalainen et al, 2019). Our data suggest S100A8 and S100A9 expression may predict PI response and targeting S100A8 or S100A9 may have therapeutic value.…”

Section: Discussionmentioning

confidence: 74%

“…S100A13 has been shown to promote melanoma metastasis and chemoresistance (Azimi et al, 2014). Furthermore, several studies have reported some S100 members participated in drug resistance: higher expression of S100A8 and S100A9 leads to glucocorticoid resistance in MLL rearranged infant acute lymphoid leukemia (Spijkers-Hagelstein et al, 2012), while our previous study revealed elevated expression of S100A8 and S100A9 negatively associate with sensitivity to the BCL2 inhibitor venetoclax in AML (Karjalainen et al, 2019). Some S100 proteins (S100A3, S100A9, S100A12, and S100A13) were upregulated in normal plasma cells compared with MM cells (Zhan et al, 2002;Amit et al, 2021).…”

Section: Introductionmentioning

confidence: 72%

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

Liu

Wang

Miettinen

et al. 2021

Front. Cell Dev. Biol.

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Despite several new therapeutic options, multiple myeloma (MM) patients experience multiple relapses and inevitably become refractory to treatment. Insights into drug resistance mechanisms may lead to the development of novel treatment strategies. The S100 family is comprised of 21 calcium binding protein members with 17 S100 genes located in the 1q21 region, which is commonly amplified in MM. Dysregulated expression of S100 family members is associated with tumor initiation, progression and inflammation. However, the relationship between the S100 family and MM pathogenesis and drug response is unknown. In this study, the roles of S100 members were systematically studied at the copy number, transcriptional and protein level with patients’ survival and drug response. Copy number analysis revealed a predominant pattern of gains occurring in S100 genes clustering in the 1q21 locus. In general, gains of genes encoding S100 family members associated with worse patient survival. However, S100 gene copy number and S100 gene expression did not necessarily correlate, and high expression of S100A4 associated with poor patient survival. Furthermore, integrated analysis of S100 gene expression and ex vivo drug sensitivity data showed significant negative correlation between expression of S100 family members (S100A8, S100A9, and S100A12) and sensitivity to some drugs used in current MM treatment, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and histone deacetylase inhibitor panobinostat. Combined proteomic and pharmacological data exhibited significant negative association of S100 members (S100A4, S100A8, and S100A9) with proteasome inhibitors and panobinostat. Clinically, the higher expression of S100A4 and S100A10 were significantly linked to shorter progression free survival in patients receiving carfilzomib-based therapy. The results indicate an association and highlight the potential functional importance of S100 members on chromosome 1q21 in the development of MM and resistance to established myeloma drugs, including proteasome inhibitors.

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“…Several biomarkers of venetoclax response in AML have been proposed at the protein [BCL-XL, MCL-1, and BCL-2 33 ] and mRNA [ BCL2 , BCL2 / MCL1 ratio, BCL2A1 , CD11b , CD14 , CD68 , CD86 , CLEC7A ( CD369 ), HOX gene family members, MCL1 , S100A8 , and S100A9 9 , 34 – 37 ] levels. Of these, the monocytic signature, BCL2A1 , CD68 , CD86 , and CLEC7A were robust predictors across both BCL-2-inhibitors (venetoclax or navitoclax), different cell culture conditions, and datasets, with none performing best across all conditions (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia

et al. 2021

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The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.

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Elevated expression of S100A8 and S100A9 correlates with resistance to the BCL-2 inhibitor venetoclax in AML

Cited by 27 publications

References 15 publications

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia

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