Abstract
Transcription factors that drive non-neoplastic myelomonocytic differentiation are well characterized but have not been systematically analyzed in the leukemic context. We investigated widely used, patient-derived myeloid leukemia cell lines with proclivity for differentiation into granulocytes by retinoic acid (RA) and/or monocytes by 1,25-dihyrdroxyvitamin D3 (D3). Using K562 (FAB M1), HL60 (FAB M2), RA-resistant HL60 sublines, NB4 (FAB M3), and U937 (FAB M5), we correlated nuclear transcription factor expression to immunophenotype, G1/G0 cell cycle arrest and functional inducible oxidative metabolism. We found that myelomonocytic transcription factors are aberrantly expressed in these cell lines. Monocytic-lineage factor EGR1 was not induced by D3 (the monocytic inducer) but instead by RA (the granulocytic inducer) in lineage bipotent myeloblastic HL60. In promyelocytic NB4 cells, EGR1 levels were increased by D3, while Gfi-1 expression (which promotes the granulocytic lineage) was upregulated during D3-induced monocytic differentiation in HL60, and by RA treatment in monocytic U937 cells. Furthermore, RARα and VDR expression were not strongly correlated to differentiation. In response to different differentiation inducers, U937 exhibited the most distinct transcription factor expression profile, while similarly mature NB4 and HL60 were better coupled. Overall, the differentiation induction agents RA and D3 elicited cell-specific responses across these common FAB M1-M5 cell lines.
Highlights
Differentiation induction therapy agents like all-trans retinoic acid (RA) and 1,25-dihyrodxyvitamin D3 (D3) show promise in many cancer cells types [1,2,3]
Wild-type and RA-resistant HL60 maintained in our laboratory have a doubling time of approximately 20 h (Fig. 1A, B) and are grown in RPMI 1640 medium with 5% FBS
We investigated the phenotypic changes that result from differentiation induction therapy in the myeloid leukemia cell line panel
Summary
Differentiation induction therapy agents like all-trans retinoic acid (RA) and 1,25-dihyrodxyvitamin D3 (D3) show promise in many cancer cells types [1,2,3]. Acute myeloid leukemias (AML) are extremely heterogeneous diseases, with over 200 known AML-related cytogenic aberrations [4], RA and D3 evoke comparable responses in human myeloid leukemia cell lines, i.e. RA induces granulocytic events while D3 induces monocytic events. Lineage-determining myeloid transcription factors are well characterized for the nonmalignant case [5,6,7], systematic analysis of their expression during differentiation induction therapy in leukemia is lacking. In this study we used sequentially more mature, human myeloid leukemia cell lines K562 (FAB M1), HL60 (FAB M2), NB4 (FAB M3) and U937 (FAB M5) and compared treatment-induced expression of an ensemble of well-known transcription factors that govern myelomonocytic lineage selection
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