Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia.
Relapse in acute myeloid leukaemia (AML) is considered to result from the persistence of drug-resistant leukaemic stem and progenitor cells (LSPC) within a bone marrow 'niche' microenvironment. Identifying novel agents that have the potential to target these LSPC in their niche microenvironment will aid in the characterization of candidate agents for post-remission chemotherapy. Using an in vitro model, we found that 48-h culture with gemtuzumab ozogamicin (Mylotarg) resulted in a 34% reduction in CD34(+)CD38(-)CD123(+) LSPC number, whereas normal CD34(+)CD38(-) haemapoietic stem cells were insensitive to this agent. As there was considerable heterogeneity in LSPC response to Mylotarg treatment, various factors potentially underpinning the differential response were assessed. LSPC that overexpressed CD33 (P=0.01), which were P-glycoprotein-negative (P=0.008) and with internal tandem duplication (ITD) of the FLT3 gene (FLT3/ITD) status (P=0.006) responded better to Mylotarg treatment. LSPC from patient samples that have these combined characteristics as well as low LSPC burden showed significantly more chemosensitivity to Mylotarg compared with all other cases (P=0.002). In multivariate analysis, LSPC burden and FLT3 status were found to be predictors of LSPC chemosensitivity to Mylotarg treatment (P<0.0001). In conclusion, we have shown heterogeneity in the LSPC compartment of AML patients underpinning differential in vitro sensitivity to Mylotarg.
Division of Haematology, University of Nottingham, Nottingham, UK. mays.jawad@nottingham.ac.uk
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Jawad
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Seedhouse
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Mony
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Grundy
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Russell
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Pallis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000617:Aminoglycosides / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000079982:Gemtuzumab; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011379:Prognosis; D063268:Sialic Acid Binding Ig-like Lectin 3; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D016179:Granulocyte Colony-Stimulating Factor; D000079982:Gemtuzumab; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3