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Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene

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POPPOVÁ Lucie PAVLOVÁ Šárka GONZALEZ Beatriz KOTAŠKOVÁ Jana PLEVOVÁ Karla DUMBOVIC Gabrijela JANOVSKA Pavlina BYSTRÝ Vojtěch PANOVSKÁ Anna BEZDĚKOVÁ Lucie MAŠLEJOVÁ Stanislava BRYCHTOVÁ Yvona DOUBEK Michael KRZYŽÁNKOVÁ Marcela BORSKÝ Marek MAYER Jiří BRYJA Vítězslav ALONSO Sergio POSPÍŠILOVÁ Šárka

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj Epigenetics
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.tandfonline.com/doi/full/10.1080/15592294.2022.2050004
Doi http://dx.doi.org/10.1080/15592294.2022.2050004
Klíčová slova WNT5A; chronic lymphocytic leukaemia; methylation; i-CLL; m-CLL
Popis Genome methylation profiles define naive-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A, encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/WNT5A-negative and IGHV-mutated/WNT5A-positive cases overlapped with m-CLL and i-CLL methylation subgroups, respectively, while most IGHV-unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.
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