Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

Abstract

The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo-keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML-MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co-cultured AML cell lines compared to the situation in wild-type AML-derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP-1, IL-6 and G-CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the cocultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro-survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells.

RNA m6A methyltransferase METTL14 promotes the procession of non‐small cell lung cancer by targeted CSF1R

“…Therefore, CSF1R was presumed to be the target of METTl14 in lung cancer. In cancer cells, aldo‐keto reductase family 1 member C1 (AKR1C1) showed robust role in tumor genesis, 39 , 40 , 41 including lung cancer. 42 , 43 , 44 Colony stimulating factor 1 receptor (CSF1R) is a cytokine which controls the production, differentiation, and function of macrophages.…”

“…Aldo‐keto reductase 1 family member C1 (AKR1C1) is a type of aldosterone reductase and plays a regulatory role in a variety of key metabolic pathways. 62 In cancer, AKR1C1 showed a robust role in cancer genesis, 39 , 40 , 41 including lung cancer. 42 , 43 , 44 Colony stimulating factor 1 receptor (CSF1R) is a cytokine which controls the production, differentiation, and function of macrophages.…”

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming

“…It is thus pertinent to explore gateways to prevent cancer cell proliferation. Although recent work reported that AKR1C1 upregulated in mesenchymal stromal cells (MSCs) to promote the survival of acute myeloid leukaemia (AML) cells, still it remains an enigma for the role of AKR1C1 in NSCLC proliferation [ 28 ].…”

Aldo-keto reductase family 1 member C1 regulates the osteogenic differentiation of human ASCs by targeting the progesterone receptor

“…Taken together, this evidence indicated that AKR1C1 could play a critical role in mediating the lineage commitment of hASCs and thus could be a potential choice for molecular target of seed cell modification in bone tissue engineering. Previous studies mainly focused on the role of AKR1C1 in tumors [ 13 – 16 , 34 ]. Its function in MSCs differentiation has been rarely documented.…”

“…Moreover, little evidence of the modulating effect of other AKR1 family members on ASCs differentiation was available in the previous studies. Recently, Yajing J et al mentioned that AKR1C1 could influence the survival of acute myeloid leukemia cells through the abnormal mesenchymal stromal cells in vitro [ 34 ]. But mesenchymal stromal cells of acute myeloid patients are in an abnormal state which have uncertain disorders.…”