Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML

Botezatu, Lacramioara; Michel, Lars; Helness, Anne; Vadnais, Charles; Makishima, Hideki; Hönes, Judith; Robert, François; Vaßen, Lothar; Thivakaran, Aniththa; Al-Matary, Yahya; Lams, Robert F.; Schütte, Judith; Giebel, Bernd; Görgens, André; Heuser, Michael; Medyouf, Hind; Maciejewski, Jaroslaw P.; Möröy, Tarik; Khandanpour, Cyrus

doi:10.1016/j.exphem.2016.05.004

Cited by 15 publications

(37 citation statements)

References 58 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also examined whether GFI1B expression level influences survival and disease progression from MDS to AML using a separate set of data. 23 , 27 Again, we could distinguish two different populations with regard to GFI1B expression (low and high) ( Figure 2F ): low expression of GFI1B correlated with poor EFS ( Figure 2G ).…”

Section: Resultsmentioning

confidence: 94%

“…Mouse leukemia was induced by transplanting Lin- BM cells that were retrovirally transduced with the MLL-AF9 oncofusion gene as well as the GFP-encoding gene, as previously described. 4 , 27 For the limiting dilution assay, different numbers of leukemic cells were retransplanted into sublethally irradiated (3 Gy) secondary recipient mice (3–4 mice/group). The frequency of functional LSCs was determined using ELDA software.…”

Section: Methodsmentioning

confidence: 99%

“…Chromatin Immunoprecipitation (ChIP) and ChIP-Seq analyses were performed as previously described. 4 , 27 Data are available from: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE88934…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

et al. 2018

Self Cite

View full text Add to dashboard Cite

Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of Gfi1b led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.

show abstract

Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…This missense variation introduces amino acid substitution from serine (GFI1-36S) to asparagine (GFI1-36N) at position 36 of protein Gfi1 [63]. In contrast to GFI1-36S, the GFI1-36N variant lacks the ability to bind its target gene that encodes the leukemia-associated transcription factor, HOXA9, and is unable to modify histone modifications that regulate HOXA9 expression [64,65]. Finally, the GFI1-36N variant depresses the HOXA9 expression by altering the epigenetic histone modification, which is consistent with the observation of frequently elevated HOXA9 expression levels in AML patients carrying the variant [64].…”

Section: Hox Transcription Factors In Cancer Predispositionmentioning

confidence: 99%

The Role of HOX Transcription Factors in Cancer Predisposition and Progression

Huang

Wei

2019

Cancers

104

View full text Add to dashboard Cite

Homeobox (HOX) transcription factors, encoded by a subset of homeodomain superfamily genes, play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Findings over the past decade have revealed that mutations in HOX genes can lead to increased cancer predisposition, and HOX genes might mediate the effect of many other cancer susceptibility factors by recognizing or executing altered genetic information. Remarkably, several lines of evidence highlight the interplays between HOX transcription factors and cancer risk loci discovered by genome-wide association studies, thereby gaining molecular and biological insight into cancer etiology. In addition, deregulated HOX gene expression impacts various aspects of cancer progression, including tumor angiogenesis, cell autophagy, proliferation, apoptosis, tumor cell migration, and metabolism. In this review, we will discuss the fundamental roles of HOX genes in cancer susceptibility and progression, highlighting multiple molecular mechanisms of HOX involved gene misregulation, as well as their potential implications in clinical practice.

show abstract

“…As a control we used GFI1-36S mice, a mouse strain containing the human GFI1 cDNA sequence at the position of the murine Gfi1 locus, as this is the mouse strain from which GFI1 -KD mice were derived. We have shown in the past that GFI1 -36S mice are functionally equivalent to murine Gfi1-WT mice (10, 13, 17, 18). In addition, they do not differ in their number of hematopoietic stem and progenitor cells (Supplementary Figure 1 A and B).…”

Section: Resultsmentioning

confidence: 99%

Dose-dependent role of Gfi1 in murine hematopoietic stem cell self-renewal and differentiation

Schuette

Thivakaran

Al-Matary

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

21Gfi1 (Growth factor independence 1) is a transcription factor that influences the stem cell 22 capacity of hematopoietic stem cells (HSCs) as well as their differentiation into the myeloid 23 and lymphoid lineage. Loss of Gfi1 impedes the repopulation capacity of HSCs and leads to a 24 block in granulocyte generation causing severe neutropenia and monocytosis. Competitive 25 transplantation assays showed that Gfi1-deficient cells were not able to reconstitute myeloid 26 and lymphoid hematopoiesis in competition with Gfi1-wildtype (GFI1-36S) cells. Low Gfi1 27 levels (GFI1-knockdown = GFI1-KD) in blasts of myelodysplastic neoplasms, acute and 28 chronic myeloid leukemia patients are associated with poor patient survival. To understand 29 how reduced levels or loss of Gfi1 contribute to hematopoiesis, we analyzed the effect of 30 GFI1-KD and Gfi1-KO on HSCs and more mature cell types in mice. GFI1-KD and Gfi1-KO 31 led to strong decrease in HSC numbers, while the numbers of early progenitors (Lin -32 Sca1 + cKit + cells) were slightly increased. Competitive transplantation assays showed that 33 GFI1-KD and Gfi1-KO HSCs can still engraft and expand, but they cannot contribute to 34 myeloid and lymphoid differentiation. 35 36 42 (granulocyte-macrophage progenitors) and CLPs (common lymphoid progenitors), while it is 43 absent in CMPs (common myeloid progenitors) and MEPs (megakaryocyte-erythroid 44 progenitors) (6). Gfi1-deficient mice are characterized by an accumulation of monocytic cells 45 and absence of granulocytes, leading to severe neutropenia and monocytosis (7, 8). Recently 46 it has been implicated that reduced levels of Gfi1 are associated with an inferior prognosis for 47 human MPN (myeloproliferative neoplasm), CML (chronic myeloid leukemia) and AML 48 (acute myeloid leukemia) patients and with an acceleration of AML development in mice (9-49 11). These studies also showed that Gfi1 regulates expression of certain oncogenes, apoptotic 50 pathways and possibly metabolic functions in a dose-dependent manner. However, it has also 51 been postulated that loss of Gfi1 negatively influences the repopulation capacity of HSCs (6, 52 12). 53We were now interested whether low levels and loss of Gfi1 indeed negatively affect the stem 54 cell and differentiation capacity of HSCs and how the seemingly contradictory findings 55 between reduced self-renewal capacity and the dose-dependent role of Gfi1 function in 56 myeloid pathogenesis could be reconciled. For the analysis we made use of Gfi1-knockout 57 (KO) mice, a mouse strain with a complete loss of Gfi1, and GFI1-knockdown (KD) mice, a 58 mouse strain in which we cloned the human GFI1 sequence into the murine Gfi1 gene locus 59 together with a Neo cassette in the opposite direction of transcription, leading to GFI1 60 expression of only 10-15% of wild-type levels (10). We show here that GFI1-KD and Gfi1-61 KO mice contain a higher number of hematopoietic progenitors (LSK cells, Lin -Sca1 + c-Kit + ), 62 but HSC (Lin -Sca1 + c-Kit + CD150 + CD48 -) numbers are ...

show abstract

Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML

Cited by 15 publications

References 58 publications

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

The Role of HOX Transcription Factors in Cancer Predisposition and Progression

Dose-dependent role of Gfi1 in murine hematopoietic stem cell self-renewal and differentiation

Contact Info

Product

Resources

About