Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature

Volpe, Giacomo; Walton, David S.; Grainger, David E.; Ward, Carl; Cauchy, Pierre; Blakemore, Daniel; Coleman, Dan; Cockerill, Peter N.; García, Paloma; Frampton, Jon

doi:10.1038/s41598-017-11718-8

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…Notably, Gfi1-null mice are viable but are characterized by severe neutropenia with compensatory monocytosis and sensorineural hearing loss (10)(11)(12). Altered GFI1 expression is found in multiple hematologic malignancies, most notably acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL) (13)(14)(15)(16)(17). Moreover, loss-offunction mutations in GFI1 cause severe congenital neutropenia (SCN) type 2 and nonimmune chronic idiopathic neutropenia (CIN) of adults, both of which predispose to AML (18,19).…”

mentioning

confidence: 99%

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

McClellan

Casey

Bareyan

et al. 2019

Molecular and Cellular Biology

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Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B’s obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.

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mentioning

confidence: 99%

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

McClellan

Casey

Bareyan

et al. 2019

Molecular and Cellular Biology

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“… 89 Recently, Volpe et al analyzed AML with normal karyotype for GFi1 expression and observed that those displaying high expression of this transcription factor have frequent FLT3 ITD and NPM1 mutations, display an FLT3 ITD signature, and exhibit high expression of some leukemia-related genes, such as HOXA9 , MEIS1 , and PBX3 . 90 At variance with the findings of Hönes et al 89 obtained in the whole AML population, in karyotype-normal AML, high GFi1 expression was associated with a worse outcome. 90 …”

Section: Lsd1mentioning

confidence: 84%

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

Castelli¹,

Pelosi²,

Testa³

2017

OTT

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Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome. In fact, genes involved in DNA demethylation (such as DNMT3A, TET2, IDH1, and IDH2) or histone methylation and demethylation (EZH2, MLL, DOT1L) are frequently mutated in primary and secondary AML. Furthermore, some histone demethylases, such as LSD1, are frequently overexpressed in AML. These observations have strongly supported a major role of dysregulated epigenetic regulatory processes in leukemia onset and development. This conclusion was further supported by the observation that mutations in genes encoding epigenetic modifiers, such as DMT3A, ASXL1, TET2, IDH1, and IDH2, are usually acquired early and are present in the founding leukemic clone. These observations have contributed to development of the idea that targeting epigenetic abnormalities could represent a potentially promising strategy for the development of innovative treatments of AML. In this review, we analyze those proteins and their inhibitors that have already reached the first stages of clinical trials in AML, namely the histone methyltransferase DOT1L, the demethylase LSD1, and the MLL-interacting protein menin.

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“…GFI1 influences prognosis of AML, CML and MPN patients in a dose-dependent manner, and in murine models of human leukemia reduced levels of GFI1 accelerated disease development (9–11, 14). AML, CML and MPN arise as a result of transformation of HSCs or early hematopoietic progenitors that still possess some degree of stem cell capacity (15).…”

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

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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 ...

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Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature

Cited by 17 publications

References 30 publications

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

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

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