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Mutations constitutively activating FLT3 kinase are detected in ∼30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal–regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein α (C/EBPα) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPα mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPα. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPα may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.

The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia-retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) selfassociation; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer. IntroductionAcute promyelocytic leukemia (APL) is a distinct disease entity within the acute myelogenous leukemia (AML). [1][2][3] In the clinic, APL has characteristic morphologic features, including hypergranular promyelocytes, and exhibits a severe bleeding tendency, which is efficiently controlled with all-trans retinoic acid (ATRA) treatment. 4 The majority of APLs feature a balanced reciprocal translocation between chromosomes 15q22 and 17q12, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes. 5 In rare cases, other fusion partners of RARA are found, such as promyelocytic leukemia zinc finger (PLZF), 6 nucleophosmin (NPM1), 7 nuclear mitotic apparatus protein (NuMA), 8 signal transducer and activator of transcription 5b, 9 protein kinase A regulatory subunit type 1A, 10 and Fip1-like 1. 11 All of the RARA fusion proteins comprise all but the first 30 amino acids of RARA fused to a variable partner at its aminoterminus. [1][2][3] It is characteristic that all fusion partners have self-association domains. In the case of PML-RARA and PLZF-RARA, aberrant recruitment of transcriptional repressors, including nuclear corepressor protein/silencing mediator of retinoid and thyroid hormone receptor (NCOR/SMRT), histone deacetylases (HDACs), 12,13 and polycomb complexes, 14,15 to the retinoic acid responsive element (RARE) leads to ectopic repression of RAR target genes. 1,2 In mouse models of RARA fusion proteins, APL-like diseases occur after a long latency, presumably because of...

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