MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE.

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line.

Insights into the molecular basis of hormone-refractory prostate cancer have principally relied on human prostate cancer cell lines, all of which were derived from patients who had already failed hormonal therapy. Recent progress in developing genetically engineered mouse prostate cancer models provides an opportunity to isolate novel cell lines from animals never exposed to hormone ablation, avoiding any potential bias conferred by the selective pressure of the castrate environment. Here we report the isolation of such a cell line (Myc-CaP) from a c-myc transgenic mouse with prostate cancer. Myc-CaP cells have an amplified androgen receptor gene despite no prior exposure to androgen withdrawal and they retain androgen-dependent transgene expression as well as androgen-dependent growth in soft agar and in mice. Reexpression of c-Myc from a hormone-independent promoter rescues growth in androgen-depleted agar but not in castrated mice, showing a clear distinction between the molecular requirements for hormone-refractory growth in vitro versus in vivo. Myc-CaP cells represent a unique reagent for dissecting discreet steps in hormone-refractory prostate cancer progression and show the general utility of using genetically engineered mouse models for establishing new prostate cancer cell lines.