Bulk RNAsequencing of wild type and LIMS1 KO THP-1 cell lines
Long-term survival in acute myeloid leukemia (AML) remains particularly poor, partly due to therapy-resistant leukemic stem cells (LSCs) that sustain disease initiation and relapse. Here, we identify LIMS1 as a previously unrecognized regulator of AML progression that controls proliferation, self-renewal, adhesion and migration of both bulk leukemic cells and LSCs. Loss of LIMS1 in AML cell lines, patient-derived xenografts (PDX) and primary human samples impairs proliferation and clonogenicity in vitro and markedly reduces engraftment and disease progression in vivo, additionally decreasing LSC frequency. Notably, healthy hematopoietic stem and progenitor cells (HSPCs) express lower levels of LIMS1 and do not exhibit any reliance on LIMS1, suggesting a leukemia-selective requirement. Transcriptomic profiling and functional assays reveal that migration, invasion, motility, and adhesion are disrupted upon LIMS1 depletion, impairing the ability of AML cells to home and colonize bone marrow and peripheral niches and explain the impaired leukemogenic potential of LIMS1-deficient cells. Interactome analysis confirm the canonical association of LIMS1 with ILK and RSU1 in AML. However, individual knockdowns of these partners do not recapitulate LIMS1 depletion, mechanistically supporting a model in which LIMS1 acts as a central scaffold coordinating multiple signalling pathways that are simultaneously disrupted upon its loss. Finally, combining LIMS1 depletion with cytarabine treatment improves the reduction of the leukemic burden in vivo, highlighting LIMS1 inhibition as a potential therapeutic strategy for AML.
Long-term survival in acute myeloid leukemia (AML) remains particularly poor, partly due to therapy-resistant leukemic stem cells (LSCs) that sustain disease initiation and relapse. Here, we identify LIMS1 as a previously unrecognized regulator of AML progression that controls proliferation, self-renewal, adhesion and migration of both bulk leukemic cells and LSCs. Loss of LIMS1 in AML cell lines, patient-derived xenografts (PDX) and primary human samples impairs proliferation and clonogenicity in vitro and markedly reduces engraftment and disease progression in vivo, additionally decreasing LSC frequency. Notably, healthy hematopoietic stem and progenitor cells (HSPCs) express lower levels of LIMS1 and do not exhibit any reliance on LIMS1, suggesting a leukemia-selective requirement. Transcriptomic profiling and functional assays reveal that migration, invasion, motility, and adhesion are disrupted upon LIMS1 depletion, impairing the ability of AML cells to home and colonize bone marrow and peripheral niches and explain the impaired leukemogenic potential of LIMS1-deficient cells. Interactome analysis confirm the canonical association of LIMS1 with ILK and RSU1 in AML. However, individual knockdowns of these partners do not recapitulate LIMS1 depletion, mechanistically supporting a model in which LIMS1 acts as a central scaffold coordinating multiple signalling pathways that are simultaneously disrupted upon its loss. Finally, combining LIMS1 depletion with cytarabine treatment improves the reduction of the leukemic burden in vivo, highlighting LIMS1 inhibition as a potential therapeutic strategy for AML.
Josep Carreras Leukaemia Research Institute / Universitat de Barcelona