ChIP-Seq/qPCR analysis in MLL-r mouse models revealed aberrant epigenetic modifications with increased H3K79me2, and decreased H3K9me3 and H3K27me3 levels in LSCs, which may account for the high expression levels of Pbx3.
The H3K4-specific demethylase KDM5B negatively regulates leukemogenesis in murine and human MLL-rearranged AML cells, demonstrating a crucial role for the H3K4 global methylome in determining LSC fate.
We demonstrate here that GSK-3 maintains the MLLleukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation.
We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase-II inhibitor VP 16.
Herein we present a novel case of acute undifferentiated leukemia with SET-NUP214 rearrangement due to the cryptic deletion of the 9q34 region producing two different types of fusion transcripts by alternative splicing and molecular characterization of the fusion transcripts by fluorescence in situ hybridization, reverse transcriptase-polymerase chain reaction, and array comparative genomic hybridization analyses.
SET-CAN associated with the t(9;9) in acute undifferentiated leukemia encodes almost the entire sequence of SET and the C-terminal two-third portion of CAN, including the FG repeat region.
SETBP1 has previously not been implicated in leukaemias; however, it encodes a protein that specifically interacts with SET, fused to NUP214 in a case of acute undifferentiated leukaemia.
This suggests that SET-CAN expression in acute undifferentiated leukemia might determine the primitive phenotype of the disease, whereas secondary genetic lesions are necessary for disease development.
Nucleotide sequence analysis revealed that the 39-kDa polypeptide corresponds to the protein encoded by the set gene, which is the part of the putative oncogene associated with acute undifferentiated leukemia when translocated to the can gene.
SET is fused to a putative oncoprotein, CAN, in AUL and is thought to regulate the transformation potential of SET-CAN by its nuclear localization and phosphorylation.
Although the function(s) of SET and SET-CAN is not known, we propose that SET plays a key role in the mechanism of leukemogenesis in acute undifferentiated leukemia, perhaps by activating CAN in nuclei and stimulating the transformation potential of SET-CAN.
SCL/TAL1 (stem cell leukemia/T-cell acute lymphoblastic leukemia [T-ALL] 1) is an essential transcription factor in normal and malignant hematopoiesis.
Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse.