Glucocorticoid-Induced Proliferation in Untreated Pediatric Acute Myeloid Leukemic Blasts

Abstract

We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC-induced proliferation, and GC-induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC-induced differentiation was not observed, while GC-induced proliferation was observed in 27% of the samples. Samples with French-American-British classification (FAB) type M5 or activating Fms-like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk.

Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

“…Furthermore, monocyte expansion observed with dexamethasone treatment could be explained by its ability to mimic IL1B activation of IL1R 43 , which stimulates their proliferation. This phenomenon has previously been observed in murine monocytes 44 as well in acute monocytic leukemia (AML, FAB subtype M5) where glucocorticoid treatment may further lead to increase in blast population fueling disease progression 45 . Therefore, understanding cytoprotective mechanisms operating in healthy cell subsets could also provide crucial insights on drug resistance mechanisms in patients.…”

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia

“…It is widely recognized that the actions of glucocorticoids are cell-type specific (Cain and Cidlowski, 2017;Gruver-Yates and Cidlowski, 2013;Klein et al, 2016), although their molecular basis has remained elusive. While certain signaling pathways appear important in glucocorticoid resistance in ALL, it is unlikely that a unifying mechanism of gene mutations accounts for resistance.…”

“…Hunger and Mullighan, 2015). Moreover, glucocorticoids are rarely efficacious in treating myeloid leukemia (Klein et al, 2016), and the mechanism of resistance in these cancers, as well as in other non-lymphoid cells, remains unclear (Cain and Cidlowski, 2017;Gruver-Yates and Cidlowski, 2013). Therefore, understanding the lymphocyte-specific mechanisms of glucocorticoid-induced apoptosis, as well as the development of resistance to this class of steroid hormones, is critical to optimizing glucocorticoid-based therapies in the clinic.…”

Epigenetic Landscape in Leukemia and Its Impact on Antileukemia Therapeutics

“…While the glucocorticoid induces apoptosis pathway is still unclear, it is a pro-apoptotic pathway exclusive to lymphoid cells despite widespread expressions of GR in most human tissues [63,64]. Glucocorticoids are rarely efficacious in treating myeloid leukemia [65]. Due to this lymphoid-specific apoptosis pathway, it is hypothesized that glucocorticoid-sensitive cells have a distinguished chromatin structure allowing for specific GR binding at GREs that glucocorticoid-resistant lymphoids, myeloid cells, and other tissue cells do not have [8,[66][67][68][69].…”

“…The actions of glucocorticoids are cell type specific [65][66][67], although the exact molecular basis for this differential function remained elusive. While certain signaling pathways resulting from ALL oncogenes appear to interfere with glucocorticoid actions resulting in resistance, epigenetic evidence suggests that in addition to genetic alterations, epigenetic factors contribute to resistance.…”