ABSTRACT
Chemotherapy resistance is the main cause of treatment failure in acute myeloid leukemia (AML) and has been related to ATP-binding cassette (ABC) transporter activity. However, the links between ABC activity, immunophenotype, and molecular AML parameters have been poorly evaluated. Moreover, the prognostic value of ABC activity, when compared to new molecular markers, is unknown. Here we investigated the links between ABC activity, as evaluated by JC-1 +/- cyclosporine A assay, and immunophenotypic, cytogenetic, molecular, and targeted next-generation sequencing features in 361 AML patients. High ABC activity was found in 164 patients and was significantly associated with less proliferating disease, an immature immunophenotype (expression of CD34, HLA-DR, CD117, CD13), and gene mutations defining AML as belonging to secondary-type ontogenic groups. Low ABC activity was associated with more mature myeloid differentiation (CD34-, cyMPO+, CD15+, CD33+) or monocytic commitment (CD64+, CD4+weak, CD14+), with NPM1 mutations, KMT2A rearrangements, and core-binding factor gene fusions, hallmarks of the de novo-type AML ontogeny. ABC activity was one of the major factors we identified using a random forest model for early prediction of AML ontogeny. In the 230 patients evaluated at diagnosis and intensively treated, high ABC activity was a predictive factor for primary resistance, and in multivariate analysis including full molecular data, an independent factor for event-free survival (P=0.0370). JC-1 +/- cyclosporine A assay could be used at diagnosis to predict AML ontogeny and to complete prognosis evaluation in addition to new molecular markers.
Subject(s)
Cyclosporine , Leukemia, Myeloid, Acute , Humans , Adult , Cyclosporine/therapeutic use , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , HLA-DR Antigens , Antigens, CD34 , Prognosis , ImmunophenotypingSubject(s)
Hearing Loss, Sensorineural/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Thrombocytopenia/congenital , Diagnosis, Differential , Female , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/metabolism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Middle Aged , Thrombocytopenia/diagnosis , Thrombocytopenia/genetics , Thrombocytopenia/metabolismABSTRACT
Bone marrow flow cytometric analysis is a powerful and rapid tool for evaluating aberrant plasma cell. In this study, we have examined the utility of multiparameter flow cytometry (MFC) in 52 patients with multiple myeloma (MM) and in 45 patients with monoclonal gammopathy with unknown significance (MGUS) into routine evaluation for the management of patients with plasma cell-related disorders. The plasma cells (PC) were identified by their light scatter distribution and reactivity patterns to CD138, CD38, and CD45. The combination of these parameters was helpful for identifying distinct subpopulations of PCs. Moderate to bright expression of CD56, CD20, CD24, CD28, and CD117 was detected in 67%, 26%, 13%, 27%, and 57% of MM cases and in 58%, 20%, 11%, 43% and 44% of MGUS cases, respectively. In MGUS group, the median percentage abnormal PCs/total PCs was 88% with 37 patients out of 45 (82%) with ratio <95%. The median ratio of the MM group was 98.9% and a ratio ≥ 95% was observed in 37 samples out of 44 (84%). In conclusion, MFC immunophenotyping of PCs has obvious clinical relevance in differential diagnosis between MM and others monoclonal gammopathies, identification of high-risk MGUS and smouldering MM, and minimal residual disease monitoring of MM. Our results showed that this tool can be easily applied in haematology laboratories.
