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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Brazilian Journal of Medical and Biological Research; v. 52, n. 6 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 16/02713-2 - Efeitos da terapia com erlotinib e gefitinib em associação ao ácido all-trans retinóico e trióxido de arsênico na leucemia promielocítica aguda: estudo in vitro, ex vivo e em modelo experimental murino.
• Beneficiário: Luciana Yamamoto de Almeida
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 11/17111-4 - Estudo in vivo do papel da hipoexpressão do gene CCAAT Enhancer binding protein alfa (CEBPA) na leucemogênese induzida pela proteína híbrida CALM/AF10
• Beneficiário: Ana Paula Alencar de Lima Lange
• Modalidade de apoio: Bolsas no Brasil - Doutorado