42 research outputs found
Mutations in KRAS and DNMT3A are not related to dependency in established tumors, in PDX acute leukemia model in vivo.
Characterization of Functional Heterogeneity of a Patient’s Acute Myeloid Leukemia Cells in a Xenograft Mouse Model.
Single-cell MultiOmic analysis of CHIP bone marrow stem and progenitor cells provides evidence of early-stage malignant transformation.
Single cell clones derived from a patient’s AML xenograft display genetic and functional heterogeneity.
Development of a bifunctional checkpoint inhibitory T cell engager (CiTE) to reverse adaptive immune escape in AML.
Copy Number Alteration (CNA) analysis in targeted sequencing data from Acute Myeloid Leukemia (AML) patients with chromosome 9q deletion.
Preclinical efficacy of Maternal Embryonic Leucine-zipper Kinase (MELK) inhibition in acute myeloid leukemia.
Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients
The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia.
Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph+ ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL