Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice

Lam, Kentson; Muselman, Alexander; Du, Randal; Harada, Yuka; Scholl, Amanda; Yan, Ming; Matsuura, Shinobu; Weng, Stephanie; Harada, Hironori; Zhang, Dong‐Er

doi:10.1182/blood-2014-02-554543

Cited by 42 publications

(36 citation statements)

References 53 publications

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“…This is in contrast to previous results using MLL-like or Meg progenitors, 29,49,71 where only 40% to 50% of identified peaks contained the Runx1 consensus motif. In agreement with other studies, approximately half of the Runx1-bound regions contained binding motifs for ETS, a known RUNX1-cooperating TF.…”

Section: Identification Of Runx1-binding Sites In Gmp-like Cells and contrasting

confidence: 55%

“…A large proportion of Runx1 target genes encode proteins that regulate adhesion and motility, although other mechanisms may be at play. Whereas some of the genes have been previously described to be direct Runx1 target genes (eg, Mpl, Hmga2, and Selp), 71,79,80 we have identified several novel Runx1 target genes, including Jam3, Plxcn1, Tek, and Ecm1. Interestingly, several common features of HSCs and Megs are known, including shared BM niches and critical interactions with endothelial cells.…”

Section: Identification Of Runx1-binding Sites In Gmp-like Cells and mentioning

confidence: 97%

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Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Behrens

Triviai

Schwieger

et al. 2016

Blood

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• Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors.• Runx1 downregulates celladhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased by more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1-deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that granulocytic/monocytic (G/M) commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSC-Meg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and G/M maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML. (Blood. 2016;127(26):3369-3381)

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Section: Identification Of Runx1-binding Sites In Gmp-like Cells and contrasting

confidence: 55%

Section: Identification Of Runx1-binding Sites In Gmp-like Cells and mentioning

confidence: 97%

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Behrens

Triviai

Schwieger

et al. 2016

Blood

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“…We identified Hmga2 as one of the most highly up-regulated mRNAs in FLs and iLIN28B adult BM CMPs compared with WT adult BM CMPs, consistent with a role as a candidate effector of Lin28b/let-7-driven regulation of CMP output. Hmga2 has been previously implicated as a regulator of myeloid progenitor cell function (Lam et al, 2014), and consistent with our results, its ectopic expression can drive adult BM and extramedullary erythropoiesis (Ikeda et al, 2011). Interestingly, this effect parallels a study wherein insertional activation of HMGA2 by a gene therapy lentivirus in a human β-thalassemia patient resulted in autonomous erythropoiesis and transfusional independence (Cavazzana-Calvo et al, 2010).…”

Section: Discussionsupporting

confidence: 76%

Developmental regulation of myeloerythroid progenitor function by the LIN28B-LET-7-HMGA2 axis

Rowe

Wang

Coma

et al. 2016

Experimental Hematology

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“…Besides regulation by the LIN28A/B-MIRLET7B axis, HMGA2 is directly regulated by RUNX1 (Lam et al, 2014;Lie et al, 2014). RUNX1 is highly expressed in patients with ALL harbouring t(4;11) and is directly activated by KMT2A-AFF1, which contributes to its transformation and unfavourable outcome (Wilkinson et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

HMGA2 as a potential molecular target inKMT2A-AFF1-positive infant acute lymphoblastic leukaemia

Eguchi‐Ishimae

Yagi

et al. 2015

Br J Haematol

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Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16INK4A . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.

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Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice

Abstract: Key Points Loss of RUNX1 by using genetic knockout or dominant-negative approaches leads to upregulation of its direct target gene Hmga2 in HSPCs. Expansion of myeloid progenitors caused by the loss of RUNX1 is rescued by loss of Hmga2, suggesting that RUNX1 functions through Hmga2.

Cited by 42 publications

References 53 publications

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Developmental regulation of myeloerythroid progenitor function by the LIN28B-LET-7-HMGA2 axis

HMGA2 as a potential molecular target inKMT2A-AFF1-positive infant acute lymphoblastic leukaemia

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