ABSTRACT
Acute promyelocytic leukemia (APL) is a relatively common form of acute myeloid leukemia (AML) that has an excellent prognosis. In contrast, secondary acute myeloid leukemias, including therapy-related AML and AML with myelodysplasia-related changes, have a relatively poor prognosis. We identified 9 cases of APL at our institution in which there was a history of chemotherapy, radiotherapy, chronic immunosuppression, or antecedent myelodysplastic syndrome. The clinical and pathologic findings in these cases of secondary APL were compared with the clinical and pathologic findings in cases of de novo APL. We found that secondary and de novo APL had abnormal promyelocytes with similar morphologic and immunophenotypic features, comparable cytogenetic findings, comparable rates of FMS-like tyrosine kinase mutations, and similar rates of recurrent disease and death. These data suggest that secondary APL is similar to de novo APL and, thus, should be considered distinct from other secondary acute myeloid neoplasms.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Myelodysplastic Syndromes/diagnosis , Neoplasms, Second Primary/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, CD/metabolism , Biomarkers, Tumor/metabolism , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Chromosome Aberrations , Combined Modality Therapy , Female , Flow Cytometry , Granulocyte Precursor Cells/metabolism , Granulocyte Precursor Cells/pathology , Humans , Immunocompromised Host , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Maryland/epidemiology , Middle Aged , Mutation , Myelodysplastic Syndromes/drug therapy , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/metabolism , Neoplasms, Second Primary/mortality , Prognosis , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Survival Rate , Young AdultABSTRACT
BACKGROUND: Dimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones. METHODOLOGY/PRINCIPAL FINDINGS: Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC(50)s in the microM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC(50). Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ. CONCLUSIONS/SIGNIFICANCE: In yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells.
