Open AccessLoss of TG‐Interacting Factor 1 decreases survival in mouse models of myeloid leukaemia
Author(s) -
Yan Ling,
Davé Utpal P.,
Engel Michael,
Brandt Stephen J.,
Hamid Rizwan
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15977
Subject(s) - haematopoiesis , cancer research , progenitor cell , biology , stem cell , myeloid , myeloid leukemia , leukemia , retinoic acid , immunology , cd34 , microbiology and biotechnology , cell culture , genetics
Abstract TG‐Interacting Factor 1 ( Tgif1 ) affects proliferation and differentiation of myeloid cells and regulates self‐renewal of haematopoietic stem cells (HSCs). To determine its impact on leukaemic haematopoiesis, we induced acute or chronic myeloid leukaemias (AML or CML) in mice by enforced expression of MLL‐AF9 or BCR‐ABL , respectively, in Tgif1 +/+ or Tgif1 −/− haematopoietic stem and progenitor cells (HSPCs) and transplanted them into syngeneic recipients. We find that loss of Tgif1 accelerates leukaemic progression and shortens survival in mice with either AML or CML. Leukaemia‐initiating cells (LICs) occur with higher frequency in AML among mice transplanted with MLL‐AF9 ‐transduced Tgif1 −/− HSPCs than with Tgif1 +/+ BMCs. Moreover, AML in mice generated with Tgif1 −/− HSPCs are chemotherapy resistant and relapse more rapidly than those whose AML arose in Tgif1 +/+ HSPCs. Whole transcriptome analysis shows significant alterations in gene expression profiles associated with transforming growth factor‐beta (TGF‐beta) and retinoic acid (RA) signalling pathways because of Tgif1 loss. These findings indicate that Tgif1 has a protective role in myeloid leukaemia initiation and progression, and its anti‐leukaemic contributions are connected to TGF‐beta‐ and RA‐driven functions.