CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting

Background The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses in 40-60% of patients, an occurrence very likely due to the persistence of leukemic stem cells that are scarcely sensitive to TKi. Nevertheless, TKi are still the only current treatment option for CML patients. Objective The aim of this study was to compare the effects of TKi belonging to different generations, imatinib and ponatinib (first and third generation, respectively), on progenitor/stem cell expansion potential and markers. Patients and Methods We used stabilized CML cell lines (KCL22, K562 and LAMA-84 cells), taking advantage of the previous demonstration of ours that cell lines contain cell subsets endowed with progenitor/stem cell properties. Primary cells explanted from CML patients were also used. The effects of TKi on the expression of stem cell related genes were compared by quantitative PCR. Flow cytometry was performed to evaluate aldehyde-dehydrogenase (ALDH) activity and the expression of cluster of differentiation (CD) cell surface hematopoietic stem cell markers. Progenitor/stem cell potential was estimated by serial colony formation ability (CFA) assay. Results Ponatinib was more effective than imatinib for the reduction of cells with ALDH activity and progenitor/stem cell potential of CML patient-derived cells and cell lines. Furthermore, ponatinib was more effective than imatinib in reducing the percentage of CD26-expressing cells in primary CML cells, whereas imatinib and ponatinib showed similar efficacy on KCL22 cells. Both drugs strongly upregulated NANOG and SOX2 in CML cell lines, but in KCL22 cells this upregulation was significantly lower with ponatinib than with imatinib, an outcome compatible with a lower level of enrichment of the stem cell compartment upon ponatinib treatment. Conclusion Ponatinib seems to target CML progenitor/stem cells better than imatinib.

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“…3a). CD26 was expressed at high levels in KCL22, but not in K562 and LAMA-84 cells, as previously reported by us and others [13,62] (Fig. 3a).…”

Section: Effects Of Imatinib and Ponatinib On Stem Cell Markers In CMsupporting

confidence: 86%

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

et al. 2020

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“…CD36 has been shown to confer chemotherapy resistance and metastasis initiation potential in cancer cells (22,23). In chronic myeloid leukemia (CML), the fatty acids transporter CD36 is associated with leukemia stem cells that evade chemotherapy by residing in the niche of adipose tissue (23,24). Furthermore, in chronic lymphoblastic leukemia (CLL) cells, STAT3 was shown to activate CD36 by binding to its promoter, facilitating fatty acid uptake (25).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia

Zhang

Yang

Vaikari

et al. 2020

Blood Cancer Discovery

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Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is signifi cantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is signifi cantly associated with decreased OS (HR: 2.51; 95% CI, 1.03-6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN-ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro , and delays leukemia progression in mice. Altogether, this study establishes APOC2-CD36 axis as a potential therapeutic target in AML. SIGnIFICAnCE: The majority of patients with AML die within fi ve years of diagnosis. We reveal that lipid transporter APOC2 is elevated in AML and promotes leukemic cell metabolism and growth via CD36, and provide preclinical evidence that targeting this pathway may be benefi cial in AML.

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“…However, its toxicity in vivo deems SSO unsuitable for therapeutic use. As an alternative strategy, inhibitory CD36-specific antibodies increase sensitivity of chronic myelogenous leukaemia cells to the first-line drug imatinib (Landberg et al, 2018 ). Etomoxir irreversibly inhibiting CPT1 and thus ß-oxidation (Abdel-aleem et al, 1994 ) and has been successfully used for the treatment of cardiac conditions (Bristow, 2000 ).…”

Section: The Role Of Fa Metabolism In Leukaemiamentioning

confidence: 99%

Epigenetic-Transcriptional Regulation of Fatty Acid Metabolism and Its Alterations in Leukaemia

et al. 2018

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In recent years fatty acid metabolism has gained greater attention in haematologic cancers such as acute myeloid leukaemia. The oxidation of fatty acids provides fuel in the form of ATP and NADH, while fatty acid synthesis provides building blocks for cellular structures. Here, we will discuss how leukaemic cells differ from healthy cells in their increased reliance on fatty acid metabolism. In order to understand how these changes are achieved, we describe the main pathways regulating fatty acid metabolism at the transcriptional level and highlight the limited knowledge about related epigenetic mechanisms. We explore these mechanisms in the context of leukaemia and consider the relevance of the bone marrow microenvironment in disease management. Finally, we discuss efforts to interfere with fatty acid metabolism as a therapeutic strategy along with the use of metabolic parameters as biomarkers.

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CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting

Cited by 51 publications

References 41 publications

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia

Epigenetic-Transcriptional Regulation of Fatty Acid Metabolism and Its Alterations in Leukaemia

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