Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes

TY - JOUR

T1 - Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes

AU - D'Altri, Teresa

AU - Schuster, Mikkel B

AU - Wenzel, Anne

AU - Porse, Bo T

N1 - © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - OBJECTIVES: Familial cases of hematological malignancies are associated with germline mutations. In particular, heterozygous mutations of SRP72 correlate with the development of myelodysplasia and bone marrow aplasia in two families. The signal recognition particle 72 kDa protein (SRP72) is part of the SRP complex, responsible for targeting of proteins to the endoplasmic reticulum. The main objective of this study is to investigate the role of SRP72 in the hematopoietic system, thus explaining why a reduced dose could increase susceptibility to hematological malignancies.METHODS: We developed an Srp72 null mouse model and characterized its hematopoietic system using flow cytometry, bone marrow transplantations, and gene expression analysis.RESULTS: Heterozygous loss of Srp72 in mice is not associated with major changes in hematopoiesis, although causes mild reductions in blood and BM cellularity and minor changes within the stem/progenitor compartment. We did not observe any hematological disorder. Interestingly, gene expression analysis demonstrated that genes encoding secreted factors, including cytokines and receptors, were transcriptionally down-regulated in Srp72+/- animals.CONCLUSIONS: The Srp72+/- mouse model only partially recapitulates the phenotype observed in families with inherited SRP72 lesions. Nonetheless, these results can provide mechanistic insights into why SRP72 mutations are associated with aplasia and myelodysplasia in humans.

AB - OBJECTIVES: Familial cases of hematological malignancies are associated with germline mutations. In particular, heterozygous mutations of SRP72 correlate with the development of myelodysplasia and bone marrow aplasia in two families. The signal recognition particle 72 kDa protein (SRP72) is part of the SRP complex, responsible for targeting of proteins to the endoplasmic reticulum. The main objective of this study is to investigate the role of SRP72 in the hematopoietic system, thus explaining why a reduced dose could increase susceptibility to hematological malignancies.METHODS: We developed an Srp72 null mouse model and characterized its hematopoietic system using flow cytometry, bone marrow transplantations, and gene expression analysis.RESULTS: Heterozygous loss of Srp72 in mice is not associated with major changes in hematopoiesis, although causes mild reductions in blood and BM cellularity and minor changes within the stem/progenitor compartment. We did not observe any hematological disorder. Interestingly, gene expression analysis demonstrated that genes encoding secreted factors, including cytokines and receptors, were transcriptionally down-regulated in Srp72+/- animals.CONCLUSIONS: The Srp72+/- mouse model only partially recapitulates the phenotype observed in families with inherited SRP72 lesions. Nonetheless, these results can provide mechanistic insights into why SRP72 mutations are associated with aplasia and myelodysplasia in humans.

U2 - 10.1111/ejh.13286

DO - 10.1111/ejh.13286

M3 - Journal article

C2 - 31254415

SN - 0902-4441

VL - 103

SP - 319

EP - 328

JO - European Journal of Haematology

JF - European Journal of Haematology

IS - 4

ER -