CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity

Bueno, Clara; Velasco-Hernández, Talía; Gutiérrez-Agüera, Francisco; Zanetti, Samanta Romina; Baroni, Matteo Libero; Sánchez-Martínez, Diego; Molina, Òscar; Closa, Adrià; Agraz-Doblás, Antonio; Marı́n, Pedro; Eyras, Eduardo; Varela, Ignacio; Menéndez, Pablo

doi:10.1038/s41375-019-0418-8

Cited by 36 publications

(34 citation statements)

References 18 publications

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“…To correlate this with gene expression patterns, we analyzed RNA-seq data from published datasets of large cohorts of infant and childhood ALL patient blasts [32,33]. In keeping with previous findings [40], MLLr leukemia cells were found to express PROM1 at much higher levels than the non-MLLr cohort (Fig. 1c).…”

Section: Mllr Leukemia Cell Lines and Primary All Blasts Show Heterogsupporting

confidence: 67%

“…The mechanism of PROM1 regulation is of relevance when considering the fetal cell of origin of infant MLL-AF4 ALL, which invariably originates in utero. CD133 is expressed during normal fetal hematopoiesis primarily in hematopoietic stem cells (HSCs) and early progenitors (multipotent progenitors (MPPs) and lymphoid-primed MPPs) [36,40]. This is consistent with a permissive environment for MLL-AF4 binding at PROM1, if the leukemia was initiated in any of these cell types.…”

Section: Discussionmentioning

confidence: 68%

“…One question which arises from our work is why CD133 is expressed in some MLLr leukemias and not others. It is possible that this simply reflects the initial CD133 status of the cell of origin, as many stem and early progenitor cells are known to express CD133 while later progenitor and more mature B cells do not [36,40,47,48]. Another possibility is that the MLL-FP itself has the ability to bind and cause aberrant upregulation of PROM1.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that non-MLLr leukemias can also be CD133+ (see Fig. 1b and [40,50,51]), as are many stem cells [36,40], in the absence of an MLL-FP to drive expression. We identified MLL binding at the PROM1 promoter in normal fetal CD34+ stem and progenitor cells ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…One important question is whether CD133 could be a useful therapeutic target. Since CD133 is expressed on both fetal and adult HSCs, it may be difficult to target CD133+ blasts without impacting normal HSCs [40]. One approach that has been proposed is to combine CD133 targeting with a second marker found on ALL blasts such as CD19 [4].…”

Section: Discussionmentioning

confidence: 99%

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H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

et al. 2020

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MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

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Section: Mllr Leukemia Cell Lines and Primary All Blasts Show Heterogsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

et al. 2020

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Recent advances in targeted protein degraders as potential therapeutic agents

et al. 2023

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Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

Elahi

Heidary

Hadiloo

et al. 2021

Stem Cell Rev and Rep

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Graphical abstract Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative “off-the-shelf” carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

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CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity

Cited by 36 publications

References 18 publications

H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Recent advances in targeted protein degraders as potential therapeutic agents

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

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