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Chronic Myeloid Leukemia
CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting
Niklas Landberg,1 Sofia von Palffy,1 Maria Askmyr,1 Henrik Lilljebjörn,1 Carl Sandén,1 Marianne Rissler,1 Satu Mustjoki,2 Henrik Hjorth-Hansen,3 Johan Richter,4 Helena Ågerstam,1 Marcus Järås1 and Thoas Fioretos1
1Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Sweden; 2Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Finland; 3Department of Hematology, St Olavs Hospital, Trondheim, Norway and 4Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
ABSTRACT
Tyrosine kinase inhibitors (TKIs) are highly effective for the treat- ment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low effi- cacy in eradicating the leukemic stem cells responsible for disease main- tenance and relapse upon drug cessation. Herein, we performed ribonu- cleic acid sequencing of flow-sorted primitive (CD34+CD38low) and pro- genitor (CD34+CD38+) chronic phase CML cells, and identified transcrip- tional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting anti- bodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitiv- ity that can be effectively targeted and killed using an anti-CD36 anti- body.
Introduction
Chronic myeloid leukemia (CML) arises when a reciprocal t(9;22) translocation, generating the BCR/ABL1 fusion gene, occurs in a hematopoietic stem cell (HSC).1,2 Currently, the disease is often controlled by daily administered tyrosine kinase inhibitors (TKIs) and patients rarely progress into an accelerated phase or blast crisis.3 However, BCR/ABL1 transcripts are still detectable during treatment, even in the majority of patients with complete clinical and cytogenetic responses.4 Among TKI- treated patients with undetectable minimal residual disease (MRD), 40-60% lose their molecular remission after TKI cessation.5 This is generally believed to be caused by CML stem cells, which are partially resistant to TKI treatment.6-8 Even patients with undetectable residual disease have been shown to harbor primitive CML cells.9 These primitive CML cells reside within the CD34+CD38low population, and have been shown by us and others to express both IL1RAP and CD26.10-14 However, the exact immunophenotype of these primitive CML cells is not clearly defined, and the identification of additional cell surface molecules on primitive CML cells may trans- late into new therapeutic opportunities.
Herein, we performed ribonucleic acid (RNA) sequencing of CML CD34+CD38low cells, and identified CD36 and the leptin receptor (LEPR) as being specifically upreg- ulated on primitive CML cells compared to corresponding normal bone marrow (NBM) cells. We further demonstrate that the CD36 expressing subpopulation of primitive CML cells is less sensitive to imatinib treatment, and that CD36 antibodies can induce selective killing of CML cells by antibody-dependent cellular cytotoxicity
Ferrata Storti Foundation
Haematologica 2018 Volume 103(3):447-455
Correspondence:
niklas.landberg@med.lu.se or thoas.fioretos@med.lu.se
Received: April 10, 2017.
Accepted: December 18, 2017. Pre-published: December 28, 2017.
doi:10.3324/haematol.2017.169946
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/447
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