Choosing the Right Cell Line for Acute Myeloid Leukemia (AML) Research

Skopek, Rafał; Palusińska, Małgorzata; Kaczor-Keller, Katarzyna; Pingwara, Rafał; Papierniak-Wygladala, Anna; Schenk, Tino; Lewicki, Sławomir; Zelent, Arthur; Szymański, Łukasz

doi:10.3390/ijms24065377

Cited by 28 publications

(11 citation statements)

References 221 publications

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“…We measured the myeloid‐monocytic lineage differentiation marker CD11b levels after BPTF or SMARCA5 KO in three AML cell lines: THP‐1, SET2, and U937. These cell lines express CD11b (Fig EV2A ) and are known to exhibit significant CD11b upregulation during differentiation (Chanput et al , 2014 ; Fiskus et al , 2021 ; Skopek et al , 2023 ). Interestingly, while BPTF and SMARCA5 KO did not affect CD11b levels in THP‐1 and SET2 cells, they did induce differentiation in U937 cells (Fig EV2B ).…”

Section: Resultsmentioning

confidence: 99%

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Radzisheuskaya,

Peña‐Rømer,

Lorenzini

et al. 2023

The EMBO Journal

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Efficient treatment of acute myeloid leukemia (AML) patients remains a challenge despite recent therapeutic advances. Here, using a CRISPRi screen targeting chromatin factors, we identified the nucleosome‐remodeling factor (NURF) subunit BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well‐studied PHD2‐BROMO chromatin reader domains of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

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Section: Resultsmentioning

confidence: 99%

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Radzisheuskaya,

Peña‐Rømer,

Lorenzini

et al. 2023

The EMBO Journal

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“…U937 is classified as FAB M5 acute monocytic leukemia; K‐562 is derived from a patient with blastic crisis after a chronic myeloid leukemia; KG1a is a FAB M1 cell line; HL‐60 is a FAB M2, acute myeloblastic leukemia with maturation. These cell lines are useful for studying how chemotherapeutics affect patients (Jensen et al 2015; Skopek et al 2023).…”

Section: Resultsmentioning

confidence: 99%

The antitumor effects of WNT5A against hematological malignancies

Bueno

Saad

Roversi

2023

J. Cell Commun. Signal.

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The bone marrow (BM) microenvironment (niche) is abnormally altered in acute myeloid leukemia (AML), leading to deficient secretion of proteins, soluble factors, and cytokines by mesenchymal stromal cells (MSC) that modifies the crosstalk between MSC and hematopoietic cells. We focused on a WNT gene/protein family member, WNT5A, which is downregulated in leukemia and correlated with disease progression and poor prognosis. We demonstrated that WNT5A protein upregulated the WNT non-canonical pathway only in leukemic cells, without modulating normal cell behavior. We also introduced a novel WNT5A-mimicking compound, Foxy-5. Our results showed reduction of crucial biological functions that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy, as well as G0/G1 cell cycle arrest. Additionally, Foxy-5 induced early-stage macrophage cell differentiation, a crucial process during leukemia development. At a molecular level, Foxy-5 led to the downregulation of two overexpressed leukemia pathways, PI3K and MAPK, which resulted in a disarrangement of actin polymerization with consequent impairment of CXCL12-induced chemotaxis. Notably, in a novel tri-dimensional bone marrow-mimicking model, Foxy-5 led to reduced leukemia cell growth and similar results were observed in a xenograft in vivo model. Overall, our findings highlight the pivotal role of WNT5A in leukemia and demonstrate that Foxy-5 acts as a specific antineoplastic agent in leukemia, counterbalancing several leukemic oncogenic processes related to the crosstalk in the bone marrow niche, and represents a promising therapeutic option for AML.

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“…For example, despite M07e and WSU-AML cells both possessing the C/G fusion, WSU-AML cells are 4-fold more sensitive to BRG1 inhibition than M07e. The reason for this differential sensitivity is unclear, though M07e has a secondary NRAS mutation that is not normally seen in C/G AML samples that may have been acquired to facilitate growth in vitro 22 . Additional patient-derived cell lines and murine models are needed to investigate this difference and determine whether C/G AML patients may respond differently to BRG1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy

Kaonis,

Smith,

Katiyar

et al. 2023

Preprint

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Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias; however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G-transduced cells with Polycomb Repressive Complex 2 (PRC2) sites in control cord blood cells identifies MYCN, ZFPM1, ZBTB16 and LMO2 as direct C/G targets. Transcriptomic analysis of a large pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identify BRG1/SMARCA4 as a vulnerability in C/G AML. BRG1 profiling in C/G patient-derived cell lines shows that the CBFA2T3 locus is a binding site. Treatment with clinically-available BRG1 inhibitors reduces fusion levels and downstream C/G targets including N-MYC, resulting in C/G leukemia cell death and extending survival in a murine xenograft model.

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Choosing the Right Cell Line for Acute Myeloid Leukemia (AML) Research

Cited by 28 publications

References 221 publications

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

The antitumor effects of WNT5A against hematological malignancies

Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy

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