THE POTENTIAL INTERPLAY BETWEEN CRLF2 AND MEF2C IN T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA
Details
- Presentation type: DR - Doctoral Student
- Track: Molecular Biology
- Keywords: Leukaemia; gene expression; CRLF2; MEF2C;
- 1 Division of Clinical Research / Research Centre / INCa (Instituto Nacional de Câncer)
- 2 Division of Clinical Research, Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA), Rio de Janeiro, Brazil
- 3 Pesquisa Clínica / INSTITUTO NACIONAL DE CANCER / Instituto Nacional de Câncer
- 4 Research Centre, Instituto Nacional de Câncer - INCA / INCA
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Log in Abstract
INTRODUCTION AND OBJECTIVE. CRLF2 overexpression is a molecular biomarker associated with increased risk of relapse in T-cell acute lymphoblastic leukaemia (T-ALL). Our group has recently shown that this alteration is significantly associated with mutations leading to the stabilization of intracellular NOTCH1 (NOTCH1-PEST/FBXW7). The molecular mechanisms underlying CRLF2 dysregulation have not been identified in T-ALL yet, therefore we aim to identify and further investigate those mechanisms. MATERIAL AND METHOD. Controlled access data of T-ALL samples from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and public data on human cell lines from the Cancer Cell Line Encyclopedia (CCLE) were analysed in this study. Patients data were categorised according to clinical-demographic, T-ALL maturational, molecular and CRLF2 gene expression profiles. RNA-seq, WES and cell lines data of H3K27ac ChIP-seq were evaluated. RESULTS AND CONCLUSION. Two hundred and sixty-four T-ALL cases were grouped into CRLF2 expression quartiles with patients located in the upper quartile being considered CRLF2-high (n = 65) and the remainder, CRLF2-low group (n = 199). CRLF2-high was observed in 65.22% (15/23) and it was much more frequent in ETP (p = 7.579e-06) than in non-ETP patients. In addition, by analysing human T-ALL cell lines we identified LOUCY (a classical ETP-ALL), MOLT13 and ALL-SIL (more mature T-ALLs subtype) as those with higher CRLF2 expression levels. ETP-ALL is the most immature T-ALL subtype, has a unique gene expression profile and is associated with overexpression of some transcription factors, including MEF2C. Similarly, CRLF2-high patients showed a MEF2C high expression profile (p = 8.266e-06), even when ETP patients were excluded (p = 0.0029). This finding suggests that MEF2C might be associated with the dysregulation of CRLF2 expression in T-ALL. Akin to our previous observation that NOTCH1 activating mutations are associated with CRLF2-high and considering that MEF2C may play a synergistic role with NOTCH1 activation, we observed that patients with coexisting NOTCH1/FBXW7 mutations and MEF2C overexpression exhibited a higher CRLF2 expression than wild-type or NOTCH1-mutated-only cases (p = 0.0021). In addition, H3K27ac data from LOUCY and ALL-SIL revealed transcriptional activity in the CRLF2 promoter and adjacent regions where we observed MEF2C binding sites. In summary, CRLF2-high is frequently found in ETP-ALL and this transcriptional dysregulation is associated with both the presence of NOTCH1 activating mutations and MEF2C overexpression. Our preliminary results suggest a regulatory role for MEF2C in CRLF2 abnormal transcriptional control in the T-ALL scenario.
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Ana Luiza Tardem Maciel
Olá, claro. Na LLA-T já foram identificadas algumas mutações que levam a ativação constitutiva da via NOTCH1, sendo elas: mutações no domínio de heterodimerização de NOTCH1 e mutações no domínio PEST deste gene. Essas últimas, juntamente com mutações no gene FBXW7 fazem com que a subunidade intracelular de NOTCH1, que é a unidade transcricional deste receptor, seja estabilizada através da sua não degradação. No nosso estudo anterior, nós vimos que estas mutações que levam a estabilização da proteína intracelular de NOTCH1 (ICN1) estão associadas a maior expressão de CRLF2 nos pacientes com LLA-T.
MARIANA STELLING
Obrigada pela reposta, Ana Luiza! Há uma hipótese de como acontece essa associação entre ICN1 e CRLF2?
Ana Luiza Tardem Maciel
Sim. ICN1 forma uma complexo no núcleo da célula e, este complexo que vai ser responsável pela atividade transcricional de NOTCH1. ICN1 não tem capacidade de ligação ao DNA, ele precisa de uma proteína, neste complexo, capaz de se ligar ao DNA. Alguns estudos sugerem que MEF2C e NOTCH1 tenham um papel sinérgico em outros modelos (se eu não me engano, de células cardíacas). Como encontramos a associação de CRLF2 com MEF2C na LLA-T, nós hipotetizamos que MEF2C possa agir como unidade transcricional do complexo de NOTCH1 nestes pacientes e, que a regulação de CRLF2 ocorra a partir da superexpressão de MEF2C e da ativação constitutiva de NOTCH1, mas é claro, precisamos de ensaios funcionais pra mostrar isso.