C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor

Genua, Cristina Di; Valletta, Simona; Buono, Mario; Stoilova, Bilyana; Sweeney, Connor; Rodríguez-Meira, Alba; Grover, Amit; Drissen, Roy; Meng, Yiran; Beveridge, Ryan; Aboukhalil, Zahra; Karamitros, Dimitris; Belderbos, Mirjam E.; Bystrykh, Leonid; Thongjuea, Supat; Vyas, Paresh; Nerlov, Claus

doi:10.1016/j.ccell.2020.03.022

Cited by 22 publications

(45 citation statements)

References 73 publications

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“…A recent report showed that biallelic CEBPA mutation combined with heterozygous mutation in GATA2 induce EL in mice. 50 In these mutant mice, myeloid progenitors, which ectopically expressed erythroid TFs including GATA1, underwent malignant transformation. Thus, during EL development, disrupted balance of lineage TFs (possibly induced by LSD1) may trigger metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα

Kohrogi

Hino²,

Sakamoto³

et al. 2021

Blood Advances

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Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation–sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.

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Section: Discussionmentioning

confidence: 99%

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα

Kohrogi

Hino²,

Sakamoto³

et al. 2021

Blood Advances

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“…This erythroidpermissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemiainitiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia [32].…”

Section: Discussionmentioning

confidence: 72%

In Silico Analysis of Nonsynonumus Single Nucleotide Polymorphisms(nsSNPs) in Human GAAGene

2021

SUDORJ

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GATA2 or GATA-binding factor 2 is a transcription factor, which regulates the expression of genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming lymphatic system-forming, and other tissue-forming stem cells. GATA2 protein is encoded by the GATA2 gene which often suffers germ line and somatic mutations which lead to a wide range of familial and sporadic diseases. Association of data including protein and genetic interactions, pathways, co-expression, co-localization and protein domain similarity were predicted using Gene MANIA software. This gene was investigated in NCBI database and the Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) were analyzed by computational software, (SIFT, PROVEAN, Polyphen-2, SNPs & GO, PHD-SNPs, I-Mutant and MUpro). The Protein structural analysis was done by modelling of amino acid substitutions using Project Hope for all predicted pathological polymorphisms. GeneMANIA results showed that GATA 2 gene was associated with 20 other genes. It interacts mainly with ZFPM1 gene (Zinc Finger Protein), FOG family member 1and HDAC5 histone deacetylase5. A total of 246 nsSNPs were obtained from the SNPs database in NCBI consisting of 47 Deleterious predicted by SIFT software. Using PROVEAN 41 SNPs were predicted to have deleterious effect, 17 SNPs were predicted to be damaging by (Polyphen- 2), while 4 SNPs were benign, 14 SNPs were found to be disease related using SNPs&GO and 30 SNPS were found to be disease related using PHD- SNP. By using I-MUTANT and MUPRO software the stability of the protein was predicted. From the results of SIFT, PROVEAN and PolyPhen-2 with respect to PHD-SNPs and SNPs&GO software programs, 6 nsSNPs (rs148942346 (R344I), rs371096438 (P385N), rs387906629 (R398W), rs387906629 (R384W), rs387906633 (C359R) and rs387906633 (C373R)) were predicted to be deleterious, damaging, affecting the protein stability and related to the formation of a disease variants. These results might be beneficial for a precise diagnosis of GATA2 deficiency and related myeloid neoplasm.

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“… 17 , 19 A recent mouse model demonstrated that bi-allelic Cebpa mutations led to myeloid leukemia development and that an additional Gata2 mutation enhanced leukemogenesis with a subset of triple transgenic mice (40%) developing leukemia with erythroid and myeloid features. 101 Interestingly, the identified leukemia-initiating cells in both models were neutrophil-monocyte progenitors and molecular characterization of this population revealed distinct function of each cooperating mutations. While bi-allelic Cepba mutations increased expression of erythroid genes, the Gata2 mutation increased chromatin accessibility at erythroid TF motifs (eg, GATA1, ZFPM1, and KLF1) and decreased it at myeloid TF motifs.…”

Section: From Tumor Viruses To Rationale Erythroleukemia Modelsmentioning

confidence: 97%

“…This idea is supported by the recent model combining bi-allelic Cebpa and Gata2 mutations. 101 Hereby, Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor ( Gata1, Klf1, and Zfmp1 ) expression and erythroid chromatin access, respectively, thereby installing ectopic erythroid potential. In addition, while bi-allelic Cebpa mutation resulted in increased erythroid transcription factors expression, it also led to increased expression of several erythroid repressors including Gata2 , Erg , or Cbfa2t3 .…”

Section: Emerging Molecular Mechanism Of Erythroleukemiamentioning

confidence: 99%

Molecular Landscapes and Models of Acute Erythroleukemia

et al. 2021

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Malignancies of the erythroid lineage are rare but aggressive diseases. Notably, the first insights into their biology emerged over half a century ago from avian and murine tumor viruses-induced erythroleukemia models providing the rationale for several transgenic mouse models that unraveled the transforming potential of signaling effectors and transcription factors in the erythroid lineage. More recently, genetic roadmaps have fueled efforts to establish models that are based on the epigenomic lesions observed in patients with erythroid malignancies. These models, together with often unexpected erythroid phenotypes in genetically modified mice, provided further insights into the molecular mechanisms of disease initiation and maintenance. Here, we review how the increasing knowledge of human erythroleukemia genetics combined with those from various mouse models indicate that the pathogenesis of the disease is based on the interplay between signaling mutations, impaired TP53 function, and altered chromatin organization. These alterations lead to aberrant activity of erythroid transcriptional master regulators like GATA1, indicating that erythroleukemia will most likely require combinatorial targeting for efficient therapeutic interventions.

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C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor

Cited by 22 publications

References 73 publications

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα

In Silico Analysis of Nonsynonumus Single Nucleotide Polymorphisms(nsSNPs) in Human GAAGene

Molecular Landscapes and Models of Acute Erythroleukemia

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