RESUMO
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is propagated by leukemic stem cells (LSCs), often characterized by deregulated Wnt signaling. We previously showed that the central transcriptional mediator of Wnt signaling LEF1 is able to cause AML in mice and acts as an independent prognostic factor in normal karyotype AML. Here, we show that treatment naïve normal karyotype AML as well as samples AML LSCs predominantly express the long ß-catenin-binding isoform of LEF1 in sharp contrast to normal human hematopoietic stem cells, which lack expression of the long isoform, but express the short N-terminally truncated isoform with loss of the ß-catenin-binding site. Gene expression and ChiP-Seq analyses in mice linked the long isoform to Wnt-ß-catenin signaling and oncogenic pathways, the N-terminally truncated isoform to stemness associated genes. Approaches impairing binding of LEF1 to ß-catenin significantly impaired AML growth, but spared normal hematopoietic stem cells. This report now demonstrates a striking difference of LEF1 isoform expression between normal and AML cells, contributing to higher vulnerability of leukemic cells to approaches targeting ß-catenin/LEF1 interaction.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Mutação , Células-Tronco Neoplásicas/patologia , Animais , Biomarcadores Tumorais , Carcinogênese , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Células-Tronco Neoplásicas/metabolismo , Isoformas de Proteínas , Via de Sinalização Wnt , beta CateninaRESUMO
Acute leukemia is initiated and maintained by leukemia stem cells (LSCs) and therefore there is great interest to develop innovative therapeutic approaches which target LSCs. Here we show that mesoporous silica nanoparticles (MSNs) functionalized with succinic anhydride, tagged with an anti-B220 antibody and loaded with the anthracycline daunorubicin are efficiently incorporated into murine B220-positive AML LSCs and preferentially kill these cells in comparison to B220-negative AML LSCs in vitro. Furthermore, short - term treatment of the AML LSCs with these MSNs before transplant significantly delayed leukemia development in recipient mice. These data demonstrate that targeting of AML LSCs can be improved by using functionalized and antigen directed MSNs as carriers for anti-leukemic drugs.
