Low-density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia

Floeth M; Elges S; Gerss J; Schwöppe C; Kessler T; Herold T; Wardelmann E; Berdel WE; Lenz G; Mikesch JH; Hartmann W; Schliemann ;, Angenendt L

Abstract

The low-density lipoprotein receptor (LDLR) is a membrane receptor thatmediates the endocytosis of low-density lipoprotein (LDL). Uptake of LDLhas been proposed to contribute to chemotherapy resistance of acute mye-loid leukaemia (AML) cell linesin vitro. In the present study, we analysedLDLR expression and survival using bone marrow biopsies from 187 inten-sively treated patients with AML. Here, increasing LDLR expression wasassociated with decreasing overall (584%, 442%, and 244%;P=00018),as well as event-free survival (417%, 181%, and 143%;P=00077), andan increasing cumulative incidence of relapse (339%, 551%, and 714%;P=00011). Associations of LDLR expression with survival were confirmedin  557  intensively  treated  patients  from  two  international  validationcohorts. In the analytic and validation cohorts, LDLR expression remainedassociated with outcome in multivariable regression analyses including theEuropean LeukemiaNet genetic risk classification. Thus, LDLR predicts out-come of patients with AML beyond existing risk factors. Furthermore, wefound low expression levels of LDLR in most healthy tissues, suggesting itas a promising target for antibody-based pharmacodelivery approaches inAML.Keywords:acute myeloid leukaemia, LDLR, prognostic impact, novel tar-gets, tissue microarray.IntroductionThe low-density lipoprotein receptor (LDLR) is a cell-surfaceglycoprotein that mediates the endocytosis of cholesterol-richlow-density lipoprotein (LDL).1Elevated LDLR expressionhas been described for some solid tumours and uptake ofLDL has been linked to tumour progressionin vivo.2–4Inter-estingly, AML cells have a higher LDL uptake than normalmononuclear blood cells and LDL is an important supple-ment  for  culturing  AML  cellsin  vitro.5–9Furthermore,uptake of LDL by AML cell lines has been proposed to con-tribute to chemotherapy resistancein vitro.10Given these preclinical observations, we aimed to investi-gate the clinical role of LDLR expression in AML. Wedemonstrate that LDLR is expressed in primary samples frompatients with AML and that its expression is inversely associ-ated with patient outcome independent from established riskfactors. Protein levels of LDLR are higher in patients withsecondary AML (sAML) compared tode novoAML. The lowprotein expression of LDLR in healthy human organs makesit a promising target for novel pharmacodelivery approachesin AML.Patients and methodsPatients, samples and treatmentProtein expression of LDLR was analysed in pre-therapeuticbone marrow (BM) trephines from 187 intensively treatedpatients with AML receiving intensive chemotherapy withcytarabine  and  daunorubicin  at  the  University  HospitalM€unster (UKM) between 2006 and 2016 (Table I).11Thestudy was approved by the regional Institutional ReviewBoard (2016-382-f-S and 2016-654-f-S). A cohort of inten-sively treated patients withde novoAML (n=400) from theDutch-Belgian  Hematology  Oncology  Cooperative  Group(HOVON)12,13and The Cancer Genome Atlas (TCGA) AMLcohort (n=157)14served as validation sets. Patients withacute promyelocytic leukaemia or myelodysplastic syndromeswere excluded from all cohorts. A study profile is shown inresearch paperFirst published online 8 June 2020doi: 10.1111/bjh.16853ª2020 The Authors.British Journal  of  Haematologypublished by British Society for Haematologyand John Wiley & Sons LtdBritish  Journal of  Haematology, 2021,192,494–503This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution andreproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.