Murine Models of Acute Myeloid Leukemia

Kurtz, Kristen; Conneely, Shannon E; O'Keefe, Madeleine; Wohlan, Katharina; Rau, Rachel E.

doi:10.3389/fonc.2022.854973

Cited by 5 publications

(4 citation statements)

References 192 publications

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“…To assess the efficacy of SWI/SNF inhibition against AML in vivo , we employed a syngeneic KMT2A-MLLT3 (“MLL-AF9”) leukemic model in C57BL/6 mice, which is an aggressive and immunocompetent AML model ( 54 ) with predictable latency. In vitro , leukemic cells displayed a dose-dependent inhibition of colony-forming capacity upon treatment with BRM014 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

et al. 2023

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In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of non-tumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings.

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Section: Resultsmentioning

confidence: 99%

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

et al. 2023

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“…Cond. KI Mx1-Cre; Kras G12D/+ Anemia, leukocytosis, splenomegaly, and myeloid hyperplasia in BM Aggressive MPN [ 25 , 29 ] Kras A146T – Het. Cond.…”

Section: Modeling Ras Mutations and Their Cooperation With Other Gene...mentioning

confidence: 99%

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Alawieh,

Cysique-Foinlan,

Willekens

et al. 2024

Blood Cancer J.

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NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.

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“…Further testing in humanized AML mouse models would provide stronger evidence for the siRNA as an immunotherapy. A challenge with studying the role of the immune system in leukemia progression is that AML xenograft models cannot recapitulate the immune phenotype observed in immunocompetent mice and humans because engraftment of human AML is not possible without T-cells, B-cells, and NK cells ablation [ 71 ].…”

Section: Application Of Nucleic Acid Therapeutics To Myeloid Malignan...mentioning

confidence: 99%

Nucleic acid therapeutics as differentiation agents for myeloid leukemias

Kovecses,

Mercier,

McKeague

2024

Leukemia

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Differentiation therapy has proven to be a success story for patients with acute promyelocytic leukemia. However, the remaining subtypes of acute myeloid leukemia (AML) are treated with cytotoxic chemotherapies that have limited efficacy and a high likelihood of resistance. As differentiation arrest is a hallmark of AML, there is increased interest in developing differentiation-inducing agents to enhance disease-free survival. Here, we provide a comprehensive review of current reports and future avenues of nucleic acid therapeutics for AML, focusing on the use of targeted nucleic acid drugs to promote differentiation. Specifically, we compare and discuss the precision of small interfering RNA, small activating RNA, antisense oligonucleotides, and aptamers to modulate gene expression patterns that drive leukemic cell differentiation. We delve into preclinical and clinical studies that demonstrate the efficacy of nucleic acid-based differentiation therapies to induce leukemic cell maturation and reduce disease burden. By directly influencing the expression of key genes involved in myeloid maturation, nucleic acid therapeutics hold the potential to induce the differentiation of leukemic cells towards a more mature and less aggressive phenotype. Furthermore, we discuss the most critical challenges associated with developing nucleic acid therapeutics for myeloid malignancies. By introducing the progress in the field and identifying future opportunities, we aim to highlight the power of nucleic acid therapeutics in reshaping the landscape of myeloid leukemia treatment.

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Murine Models of Acute Myeloid Leukemia

Cited by 5 publications

References 192 publications

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Nucleic acid therapeutics as differentiation agents for myeloid leukemias

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