Cutting Off Leukemogenesis: Hydra-like Plasticity of Mature Leukemic Cells

Bamezai, Shiva; Buske, Christian

doi:10.1016/j.stem.2019.07.005

Cited by 3 publications

(1 citation statement)

References 10 publications

(11 reference statements)

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“…In principle, if leukemia maturation is unidirectional and irreversible then relapse must arise from selection of immature leukemia cells with pre-existing mutations that prevent therapy-induced maturation. However recent analysis of a mouse AML model driven by reversible RNAi-mediated knockdown of the myeloid transcription factor PU.1 demonstrated interconversion between an immature leukemogenic state and a mature non-leukemogenic state based on PU.1 suppression or restoration respectively 33 , 34 . Similarly, ATRA-induced APL maturation can also be reversed upon treatment cessation 33 .…”

Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

et al. 2021

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Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

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Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

et al. 2021

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Myeloid Differentiation Increases Resistance of Leukemic Cells to TRAIL-Induced Death by Reducing the Expression of DR4 and DR5 Receptors

Lomovskaya

Kobyakova²,

Сенотов³

et al. 2023

Biochem. Moscow Suppl. Ser. A

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Therapeutic targeting of leukemia stem cells in acute myeloid leukemia

Barbosa

Deshpande

2023

Front. Oncol.

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One of the distinguishing properties of hematopoietic stem cells is their ability to self-renew. Since self-renewal is important for the continuous replenishment of the hematopoietic stem cell pool, this property is often hijacked in blood cancers. Acute myeloid leukemia (AML) is believed to be arranged in a hierarchy, with self-renewing leukemia stem cells (LSCs) giving rise to the bulk tumor. Some of the earliest characterizations of LSCs were made in seminal studies that assessed the ability of prospectively isolated candidate AML stem cells to repopulate the entire heterogeneity of the tumor in mice. Further studies indicated that LSCs may be responsible for chemotherapy resistance and therefore act as a reservoir for secondary disease and leukemia relapse. In recent years, a number of studies have helped illuminate the complexity of clonality in bone marrow pathologies, including leukemias. Many features distinguishing LSCs from normal hematopoietic stem cells have been identified, and these studies have opened up diverse avenues for targeting LSCs, with an impact on the clinical management of AML patients. This review will discuss the role of self-renewal in AML and its implications, distinguishing characteristics between normal and leukemia stem cells, and opportunities for therapeutic targeting of AML LSCs.

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Cutting Off Leukemogenesis: Hydra-like Plasticity of Mature Leukemic Cells

Cited by 3 publications

References 10 publications

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

Myeloid Differentiation Increases Resistance of Leukemic Cells to TRAIL-Induced Death by Reducing the Expression of DR4 and DR5 Receptors

Therapeutic targeting of leukemia stem cells in acute myeloid leukemia

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