CCAAT/enhancer-binding protein alpha (CEBPA) gene haploinsufficiency does not alter hematopoiesis or induce leukemia in Lck-CALM/AF10 transgenic mice

Author(s)

Lange, A. P. ^{[1, 2]} ; Almeida, L. Y. ^{[1, 2]} ; Araujo Silva, C. L. ^{[1, 2]} ; Scheucher, P. S. ^{[1, 2]} ; Chahud, F. ^[3] ; Krause, A. ^[4] ; Bohlander, S. K. ^[5] ; Rego, E. M. ^{[1, 2, 6]}

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, Div Hematol, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Ctr Terapia Celular, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Patol & Med Legal, Ribeirao Preto, SP - Brazil

^[4] Univ Fed Santa Maria, Lab Anal Clin Vet, Santa Maria, RS - Brazil

^[5] Univ Auckland, Dept Mol Med & Pathol, Leukaemia & Blood Canc Res Unit, Auckland - New Zealand

^[6] Univ Sao Paulo, Fac Med, Div Hematol, LIM31, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Brazilian Journal of Medical and Biological Research; v. 52, n. 6 2019.
• Web of Science Citations: 0

Abstract

Although rare, CALM/AF10 is a chromosomal rearrangement found in immature T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia, and mixed phenotype acute leukemia of T/myeloid lineages with poor prognosis. Moreover, this translocation is detected in 50% of T-ALL patients with gamma/delta T cell receptor rearrangement, frequently associated with low expression of transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). However, the relevance of CEBPA low expression for CALM/AF10 leukemogenesis has not yet been evaluated. We generated double mutant mice, which express the Lck-CALM/AF10 fusion gene and are haploinsufficient for the Cebpa gene. To characterize the hematopoiesis, we quantified hematopoietic stem cells, myeloid progenitor cells, megakaryocyte-erythrocyte progenitor cells, common myeloid progenitor cells, and granulocyte-macrophage progenitor cells. No significant difference was detected in any of the progenitor subsets. Finally, we tested if Cebpa haploinsufficiency would lead to the expansion of Mac-1+/B220+/c-Kit+ cells proposed as the CALM/AF10 leukemic progenitor. Less than 1% of bone marrow cells expressed Mac-1, B220, and c-Kit with no significant difference between groups. Our results showed that the reduction of Cebpa gene expression in Lck-CALM/AF10 mice did not affect their hematopoiesis or induce leukemia. Our data corroborated previous studies suggesting that the CALM/AF10 leukemia-initiating cells are early progenitors with lymphoid/myeloid differentiating potential. (AU)

• FAPESP's process: 16/02713-2 - Effects of erlotinib and gefitinib therapy in combination with all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: in vitro, ex vivo and murine experimental model studies.
• Grantee: Luciana Yamamoto de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/17111-4 - In vivo study of the role of CCAAT Enhancer binding protein alpha (CEBPA)gene hipoexpression in the leukemogenesis induced by the CALM/AF10 hybrid protein.
• Grantee: Ana Paula Alencar de Lima Lange
• Support Opportunities: Scholarships in Brazil - Doctorate