Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

Mesuraca, Maria; Amodio, Nicola; Chiarella, Emanuela; Scicchitano, Stefania; Aloisio, Annamaria; Codispoti, Bruna; Lucchino, Valeria; Montalcini, Ylenia; Bond, Heather M.

doi:10.3390/molecules23082060

Cited by 6 publications

(7 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SATB1 is a global genomic organizer that participates in activation and inactivation of genes and the differentiation of embryonic stem cells, thus is implicated in a variety of cancers and cancer progression [4, 5, 15, 17, 22, 29–31]. Up-regulation of SATB1 was found in many epithelial tumors and negatively correlated with the prognostic properties and clinical outcome [6, 15, 32].…”

Section: Discussionmentioning

confidence: 99%

“…often has poor response to chemotherapy, high relapse rate and aggressive progression [2–8]. Chemotherapy for AML remained largely unchanged for decades, clinical response of targeted therapy is limited and the survival improvements over time were attributable mostly to hematopoietic stem cell transplantation (HSCT) [2, 5, 9]. New chromosomal aberrations, epigenetic changes and mutations of AML continue to be reported, and risk stratification is now based on genetic, genomic, and molecular characteristics which help determine the effect on prognosis, as well as provide new insights into the mechanisms of AML.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Luo

et al. 2019

Cancer Cell Int

View full text Add to dashboard Cite

Background Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin-remodeling protein that regulates gene expressions in different types of cancer. Up-regulation of SATB1 is linked with progression of tumors. Our previous study showed that SATB1 expression was decreased in T cell leukemia/lymphoma. The contrary roles of SATB1 in solid organ tumors and hematology malignancy may provide hints to study the function of SATB1. Methods To characterize SATB1 mRNA and protein expression in acute myeloid leukemia (AML), we performed qRT-PCR and Western blot on bone marrow mononuclear cells from 52 newly diagnosed AML patients. Stable HL-60 cell lines with knockdown of SATB1 by shRNAs sequences (HL-60 SATB1-shRNA1 and HL-60 SATB1-shRNA2) were established. Cell proliferation, cell cycle and cell invasiveness were analyzed. Murine model was established using HL-60 SATB1-shRNAs treated nude mice and tumorigenicity was compared to study the role of SATB1 in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown to investigate the mechanisms underlying the regulation of AML cell growth by SATB1. Results We found that SATB1 expression was significantly decreased in patients with AML compared to normal control, and was increased after complete remission of AML. Knockdown of SATB1 enhanced the proliferation of HL-60 cells and accelerated S phase entry in vitro, and promoted the tumor growth in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown and the differentially expressed genes were involved in NF-κB, MAPK and PI3 K/Akt signaling pathways. Nuclear NF-κB p65 levels were significantly increased in SATB1 depleted HL-60 cells. Conclusions Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation. SATB1 could be a predictor for better response to treatment in AML.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Luo

et al. 2019

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…The CB-MA9 cells (immortalized population 60-65 days) were compared to control transduced cells (control vector UMG-LV6) at 3 weeks when proliferation was still evident after this time point these cells no longer thrive. There was an evident increase in mRNA for the MA9 targets HOXA9, MEIS1 and ZNF521 [26][27][28] which was not affected by ZOL treatment.…”

Section: Zol Inhibits Cobblestone Area Formation In An In Vitro Co-culture System Of Transformed Hscs and Ms-5 Cellsmentioning

confidence: 92%

“…The MLL gene encodes for a methyltransferase protein [23,24] and when fused with partner proteins, such as AF9, the catalytic domain is lost and the aberrant fusion protein gains the ability to methylate H3K79, which results in abnormal gene expression of genes such as HOXA9 and MEIS1. Immunocompromised mice transplanted with cord blood (CB) cells transformed with the MA9 fusion gene, develop myeloid or lymphoid leukemias [25,26,27]. HSCs from foetal origin, transformed with MA9 fusion gene, develop both AML and ALL; instead bone marrow derived transfected HSCs give rise, with inferior efficacy, essentially to AML [28].…”

Section: Introductionmentioning

confidence: 99%

Zoledronic acid inhibits the growth of leukemic MLL-AF9 transformed hematopoietic cells

Chiarella

Codispoti

Aloisio

et al. 2020

Heliyon

Self Cite

View full text Add to dashboard Cite

A leukemic in vitro model produced by transducing Cord Blood derived-hematopoietic CD34 þ cells with the MLL-AF9 translocation resulting in the oncogenic fusion protein, is used to assess for sensitivity to Zoledronic acid. These cells are practically immortalized and are of myeloid origin. Proliferation, clonogenic and stromal coculture assays showed that the MLL-AF9 cells were considerably more sensitive to Zoledronic acid than normal hematopoietic CD34 þ cells or MS-5 stromal cells. The MLL-AF9 cells were notably more inhibited by Zoledronic acid when cultured as colonies in 3 dimensions, requiring cell-cell contacts compared to suspension expansion cultures. This is coherent with the mechanism of action of Zoledronic acid inhibiting farnesyl diphosphate synthase which results in a block in prenylation of GTPases such that their role in the membrane is compromised for cell-cell contacts. Zoledronic acid can be proposed to target the MLL-AF9 leukemic stem cells before they emerge from the hematopoietic niche, which being in proximity to bone osteoclasts where Zoledronic acid is sequestered can be predicted to result in sufficient levels to result in an anti-leukemic action.

show abstract

“…The MLL-AF9 fusion gene is described as playing a critical role in stem and progenitor populations and in leukemogenesis [ 8 , 9 , 10 , 11 , 12 ]. During hematopoietic cell development, MLL and AF9 wild-type proteins act as components of protein complexes leading to the transcriptional initiation (MLL) and elongation (AF9) of target genes through the methylation of specific histones, resulting in activated promoters [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Chiarella

Aloisio

Scicchitano

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

show abstract

Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

Cited by 6 publications

References 97 publications

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Zoledronic acid inhibits the growth of leukemic MLL-AF9 transformed hematopoietic cells

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Contact Info

Product

Resources

About