Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia

Zhang, Haijiao; Nakauchi, Yusuke; Köhnke, Thomas; Stafford, Melissa; Bottomly, Daniel; Thomas, Rozario; Wilmot, Beth; McWeeney, Shannon K.; Majeti, Ravindra; Tyner, Jeffrey W.

doi:10.1038/s43018-020-0103-x

Cited by 141 publications

(165 citation statements)

References 59 publications

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“…Three of these genes were confirmed in four out of five cohorts, thus representing high-fidelity ADM co-expressed genes. They were the p53 transcriptional target SAT1 , that is involved in polyamine metabolism and functions as a metabolic mediator of ferroptotic cell death ( 51 ), the BCL2 family member BCL2A1 , that has been recently shown to confer resistance to Venetoclax treatment ( 52 , 53 ), and IER5 , that regulates LPC proliferation ( 54 ) ( Figure 3B and Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

et al. 2021

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Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted in vitro by endothelial cells and vascular smooth muscle cells, and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects, ADM transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express ADM. ADM was overexpressed in AML cells versus normal CD34+ cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of ADM expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of ADM in FLT3-ITD, NPM1-mutated AML and FLT3-ITD/NPM1-mutated cases compared with wild-type ones. Moreover, ADM expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with ADM levels in the bone marrow cells of at least two AML cohorts. Moreover, ADM was upregulated in CD4+ T and CD8+ T cells from AML patients compared with healthy controls and some ADM co-expressed genes participate in a signature of immune tolerance that characterizes CD4+ T cells from leukemic patients. Overall, our study shows that ADM expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.

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Section: Resultsmentioning

confidence: 99%

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

et al. 2021

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“…They concluded by associating increased expression of monocyte markers CD14 , CD11b , CD86 , and CD68 with decreased ex vivo responsiveness to venetoclax. Among other identified biomarkers, Zhang and colleagues also implicated high expression of CD14 , as well as the monocyte-associated CLEC7A ( CD369 ), with reduced sensitivity to venetoclax 36 . We provide independent validation of these biomarkers, confirming that leukemic cells expressing high levels of CD68 , CD86 , and CLEC7A , in particular, are more resistant to BCL-2 inhibition via both venetoclax and navitoclax (Supplementary Fig.…”

Section: Discussionmentioning

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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“…Targeting NRAS mutations that confer late gilteritinib resistance offers one potential approach for combination therapy, as both MEK and PI3K inhibitors partially restored gilteritinib efficacy (Figures 3F-3J). These combinations have been proposed in AML (Traer et al, 2016;Mcmahon et al, 2019;Zhang et al, 2019Zhang et al, , 2020 and other cancers (Tricker et al, 2015;Smida et al, 2016;Morgillo et al, 2017). However, not all patients treated with gilteritinib develop RAS mutations (Perl et al, 2019), and it is unclear if the addition of these inhibitors would forestall the expansion of RAS mutations or drive early resistant cells to adopt alternative resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

et al. 2021

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Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia

Cited by 141 publications

References 59 publications

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

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

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

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