A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

Abstract

Dormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an in vitro model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) and a mammalian target of rapamycin inhibitor. The treated cells showed decreases in total RNA, Ki-67 and CD71, increased aldehyde dehydrogenase activity, forkhead box 03A (FOX03A) nuclear translocation and growth inhibition, with no evidence of apoptosis or differentiation. Using human genome gene expression profiling we identified a signature enriched for genes involved in adhesion, stemness/inhibition of differentiation and tumour suppression as well as canonical cell cycle regulation. The most upregulated gene was the osteopontin-coding gene SPP1. Dormant cells also demonstrated significantly upregulated beta 3 integrin (ITGB3) and CD44, as well as increased adhesion to their ligands vitronectin and hyaluronic acid as well as to bone marrow stromal cells. Immunocytochemistry of bone marrow biopsies of AML patients confirmed the positive expression of osteopontin in blasts near the para-trabecular bone marrow, whereas osteopontin was rarely detected in mononuclear cell isolates. Unsupervised hierarchical clustering of the dormancy gene signature in primary acute myeloid leukaemia samples from the Cancer Genome Atlas identified a cluster enriched for dormancy genes associated with poor overall survival.

Control in dormancy or eradication of cancer stem cells: Mathematical modeling and stability issues

“…This is what we observe for instance in the case of leukemia [25]. On the other hand, it cannot be disregarded that in some cases (as in breast cancer and leukemia [6,26]) CSCs do not overproliferate (cancer without disease [35], or, in situ tumor). However, even during their non-overproliferating states, CSCs remain in general distinguishable through specific markers on their surface 6 [76].…”

“…On the other hand, it cannot be disregarded that in some cases (as in breast cancer and leukemia [6,26]) CSCs do not overproliferate (cancer without disease [35], or, in situ tumor). However, even during their non-overproliferating states, CSCs remain in general distinguishable through specific markers on their surface 6 [76]. In medical research, the CSC hypothesis 7 postulates that one subpopulation of cells holds the power of initiating and regenerating cancer [28].…”

Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients

“…We found enrichment for overexpression of genes involved in heme metabolism in the resistant cohort (FDR corrected p = 0.0125) [31]. Additional genes that were overexpressed in the resistant samples (down regulated in the sensitive cohort) included those related to growth and mobility such as B3GNT7 known to be involved in cell migration and invasion and SPP1 (encoding for osteopontin) which is both a marker of poor survival in AML and related to adhesion, stemness, and differentiation [32][33][34]. Further, ANK1, a gene involved in erythropoiesis is known to be under-expressed in FLT3-ITD mutated samples, was downregulated in the midostaurin sensitive cohort regardless of mutation status [35] ( Figure 3A).…”

Salivary Osteopontin as a Potential Biomarker for Oral Mucositis

“…There is an association of higher OPN expression with a more aggressive variant of lymphoma [ 37 ]. Several other studies have confirmed the prognostic significance of OPN both in acute myeloid and lymphoid leukaemia [ 38 , 39 , 40 , 41 ]. In our study, serum OPN level showed marked overexpression at all four stages of transplantation compared to the control group.…”