TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia

Abstract

The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leuke-mogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro-inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia.

Evolution from adherent to suspension – systems biology of HEK293 cell line development

“…15 Moreover, significant changes were associated with cell adhesion, cell motility, 16 cell morphogenesis and differentiation. Noteworthy, cell adhesion was found up-17 regulated in suspension progeny cell lines and when looking into the expression 18 of the most significant differentially expressed genes (adjusted p-value <0.01) 19 amongst the cell adhesion gene set (Table S6), there are several cell adhesion 20 molecules (CAMs) found both up-and down-regulated in suspension cells com-21 pared to adherent. Remarkably, several members of the cadherin superfamily, 22 including many different protocadherins (PCDH), desmoglein 2 (DSG2) and 23 desmocollin 2 (DSC2) were found significantly up-regulated in suspension cells 24 compared to adherent cells.…”

“…higher degree of disruption of adherence junctions compared to the parental 13 HEK293 strain (data not shown), which may be important for the suspension cell 14 phenotype. 15 16 Identification of five genes with potential key roles in differences between 17 adherent and suspension human cell lines 18 Altogether nine of the previously identified 38 genes (LOX, ID1, ADAMTS1, ZIC1, 19 KCNMA1, DHRS3, RARG, COL4A6 and ARRDC4) were shown to have significantly 20 different expression levels also in an extended validation of the genes in a set of 21 63 human cell lines from the HPA database (Uhlen et al, 2017) (Figure 6). ever, in the case of four of the genes (ADAMTS1, KCNMA1, COL4A6 and ARRDC4) 23 the direction of expression between adherent and suspension cells was reversed 24…”

“…gesting more efficient catalytic activity of the DHRS3 enzyme in the adherent cell 18 lines, which may lead to retinoic acid signaling in the absence of retinoic acid, 19 resulting in a more adherent phenotype in these cell lines. 20 21…”

“…One 293E cell line is host for the production of dulaglutide 17 (TRULICITY ® ) (Lalonde and Durocher, 2017). In addition, several HEK293 cell 18 lines have been adapted to suspension growth in serum-free medium at high cell 19 density (Graham, 1987) (Garnier et al, 1994) (Côté et al, 1998), enabling large- 20 scale cultivation and bioproduction in bioreactors. Two industrially relevant 21 suspension cell lines are 293-F and 293-H (Gibco, Thermo Fisher Scientific).…”

“…cules within the desmocollin (DSC) and desmoglein (DSG) subfamilies, belonging 18 to the cell-cell adhesion gene set (GO: 0098609), are located. When analyzing 19 more local copy number variations between progeny cell lines and the parental 20 strain, some interesting loss or gain of full or partial elements compared to the 21 parental HEK293 was identified.…”