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Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.

ABSTRACT: Sal-like protein 4 (SALL4) is a transcription factor that exists in two splice isoforms, SALL4a and SALL4b, and regulates transcription in embryonic stem cells, hematopoiesis, and acute myeloid leukemia. Constitutive overexpression of SALL4 in mice induces acute myeloid leukemia. Interestingly, a potential benefit of using SALL4 to facilitate ex vivo hematopoietic stem cell expansion has been proposed. However, distinct roles for how SALL4 contributes to normal versus malignant processes remain undefined. Here we show that SALL4b is the predominant isoform in murine hematopoietic stem cells and progenitors. Overexpression of either SALL4 isoform in hematopoietic stem cells or progenitors impairs hematopoietic colony formation and expansion in vitro. Lineage-negative bone marrow overexpressing SALL4b fails to engraft and reconstitute hematopoiesis when transplanted. We found that both SALL4a and SALL4b overexpression impair hematopoiesis, in part through dose-dependent repression of BMI1. Additionally, we have identified the following potential novel SALL4 target genes in hematopoiesis: ARID5B (SALL4a and SALL4b), EZH2, and KLF2 (SALL4a). Lastly, we found that SALL4 expression is variable in acute myeloid leukemia, ranging from no expression to levels comparable to embryonic stem cells. These results show that SALL4 isoforms contribute to only a subset of acute myeloid leukemia and that overexpression of SALL4 isoforms impairs hematopoiesis through repression of BMI1. Together these data demonstrate the sensitivity of hematopoiesis to appropriately balanced SALL4 expression, highlighting the importance of regulating this dynamic in potential therapeutic applications such as ex vivo stem cell expansion.

SUBMITTER: Milanovich S

PROVIDER: S-EPMC4268405 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.

Milanovich Samuel S Peterson Jonathan J Allred Jeremy J Stelloh Cary C Rajasekaran Kamalakannan K Fisher Joseph J Duncan Stephen A SA Malarkannan Subramaniam S Rao Sridhar S

Experimental hematology 20140920 1

Sal-like protein 4 (SALL4) is a transcription factor that exists in two splice isoforms, SALL4a and SALL4b, and regulates transcription in embryonic stem cells, hematopoiesis, and acute myeloid leukemia. Constitutive overexpression of SALL4 in mice induces acute myeloid leukemia. Interestingly, a potential benefit of using SALL4 to facilitate ex vivo hematopoietic stem cell expansion has been proposed. However, distinct roles for how SALL4 contributes to normal versus malignant processes remain ...[more]

PMID: 25246269

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Project description:Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing of in vivo cutaneous wounds and closure of in vitro scratch wounds in murine embryonic fibroblast (MEF) monolayers were delayed in 129, but not B6, TG2 knockouts, relative to their wild-type counterparts, with wound closure in 129 being faster than in B6 wild-types. A single dose of exogenous recombinant wild-type TG2 to 129 TG2-/- mice or MEFs immediately post-wounding accelerated wound closure. Neutrophil and monocyte recruitment to 129 cutaneous wounds was not affected by Tgm2 deletion up to 5 days post-wounding. Tgm2 mRNA and TG2 protein abundance were higher in 129 than in B6 wild-types and increased in abundance following cutaneous and scratch wounding. Tgm1 and factor XIIA (F13A) mRNA abundance increased post-wounding, but there was no compensation by TG family members in TG2-/- relative to TG2+/+ mice in either strain before or after wounding. 129 TG2+/+ MEF adhesion was greater and spreading was faster than that of B6 TG2+/+ MEFs, and was dependent on syndecan binding in the presence, but not absence, of RGD inhibition of integrin binding. Adhesion and spreading of 129, but not B6, TG2-/- MEFs was impaired relative to their wild-type counterparts and was accelerated by exogenous addition or transfection of TG2 protein or cDNA, respectively, and was independent of the transamidase or GTP-binding activity of TG2. Rho-family GTPase activation, central to cytoskeletal organization, was altered in 129 TG2-/- MEFs, with delayed RhoA and earlier Rac1 activation than in TG2+/+ MEFs. These findings indicate that the rate of wound healing is different between 129 and B6 mouse strains, correlating with TG2 abundance, and although not essential for wound healing, TG2 facilitates integrin- and syndecan-mediated RhoA- and Rac1-activation in fibroblasts to promote efficient wound contraction.

Dataset Information

Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.

Publications

Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.

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