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Article
| Open Access
Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.
- Amy Dawson
- , Martha M. Zarou
- & G. Vignir Helgason
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Article
| Open Access
Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open Access
Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors
Leukemic stem cells (LSCs) in chronic myeloid leukemia are resistant to imatinib and therefore are a cause of relapse. The authors show that IRAK1/4-NF-κB-PD-L1 signaling is critical to mediate imatinib resistance in LSCs and that combining imatinib with blocking this signalling pathway can eliminate LSCs.
- Yosuke Tanaka
- , Reina Takeda
- & Toshio Kitamura
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Article
| Open Access
RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.
- Ryan M. Carr
- , Denis Vorobyev
- & Mrinal M. Patnaik
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Article
| Open Access
Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.
- Hu Lei
- , Han-Zhang Xu
- & Ying-Li Wu
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Article
| Open Access
Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells
Chronic myelogenous leukemia (CML)-initiating cells are resistant to kinase inhibitors. Here the authors show that deficiency of the Rap1 GTPase-activating protein Sipa1 in the tumor microenvironment releases an immune response that eradicates CML-initiating cells via interplay between stromal and T cells.
- Yan Xu
- , Satoshi Ikeda
- & Nagahiro Minato
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Article
| Open Access
Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.
- Jane Merlevede
- , Nathalie Droin
- & Eric Solary
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Article
| Open Access
Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells
Chronic myelogenous leukaemia contains a stem cell fraction and targeting this population of cells is an attractive therapeutic strategy. Here, the authors demonstrate that the stem cells take up dipeptides and that inhibiting the dipeptide transporter could reduce the number of these stem cells in mice.
- Kazuhito Naka
- , Yoshie Jomen
- & Seong-Jin Kim
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Dissecting the role of aberrant DNA methylation in human leukaemia
Chronic myeloid leukaemia is characterized by the genetic translocation t(9;22) encoding for BCR-ABL oncogene; however, the molecular mechanisms of disease progression are poorly understood. Here Amabile et al. show that aberrant methylation is promoted by BCR-ABL, driving the evolution of the disease.
- Giovanni Amabile
- , Annalisa Di Ruscio
- & Daniel G. Tenen
Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing