Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc by Angela Stoddart,

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Presentation transcript:

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc by Angela Stoddart, Jianghong Wang, Anthony A. Fernald, Theodore Karrison, John Anastasi, and Michelle M. Le Beau Blood Volume 123(2): January 9, 2014 ©2014 by American Society of Hematology

Loss of 1 Allele of Egr1, Tp53, or both genes equally accelerates Apc del/+-induced fatal anemia. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

All mice with Apc haploinsufficiency develop a macrocytic anemia with monocytosis. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

Anemia in all Apc haploinsufficient mice is caused by a block at an early erythroblast stage. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

Anemia and block in erythropoiesis is detected earlier in Egr1+/−, Apcdel/+ double heterozygous mice compared with Apcdel/+ mice. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

ENU-treated mice with Apc haploinsufficiency develop a fatal macrocytic anemia at an accelerated pace, regardless of Egr1 or Tp53 expression. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

The fatal anemia is induced by an Apc-haploinsufficient BM microenvironment (A) Kaplan-Meier survival curve of Apcfl/+ (WT) or Apcdel/+ recipients transplanted with WT, Egr1+/; Tp53+/−; Apcdel/+; or Egr1+/−, Apcdel/+BM cells. Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology

The fatal anemia is slightly accelerated by pretreatment of Apcdel/+ recipients with ENU. (A) A model showing that Apcfl/+and Apcdel/+ recipients (CD45.2+) were treated with pIpC at 2 months, ENU at 2.5 months (where indicated), and transplanted 4 weeks pos... Angela Stoddart et al. Blood 2014;123: ©2014 by American Society of Hematology