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Low expression of ZHX1 and ZHX2 impacts on the prognosis of chronic lymphocytic leukemia.

ABSTRACT: Experimental evidence points to the role of Zinc fingers and homeoboxes protein 1 and 2 (ZHX1 and ZHX2) in the development and progression of several types of cancer, including hematological malignancies. Here, we determined whether the altered expression of ZHX1 and ZHX2 has clinical implications in patients with CLL. Interestingly, CLL patients with low expression ZHX1 and ZHX2 presented higher WBC counts. Importantly, our data showed that CLL patients with cytogenetic alterations presented reduced transcriptional levels of ZHX1 and ZHX2 in comparison with patients with normal karyotype. Moreover, when stratifying CLL patients according to the karyotype prognosis value, we observed that the expression of ZHX1 and ZHX2 was significantly reduced in CLL patients presenting adverse karyotypes. Finally, we stratified patients according to the number of chromosomal aberrations and observed a negative association between ZHX1 and ZHX2 expression and the accumulation of chromosomal abnormalities in CLL patients. Our data showed that the low expression of ZHX1 and ZHX2 is associated with a worse prognosis in CLL, followed by a greater number of leukemic cells and unfavorable cytogenetics findings in the diagnosis. Further studies will be important to confirm the prognostic value of ZHX1 and ZHX2 in independent CLL cohorts.

SUBMITTER: Maciel NIG

PROVIDER: S-EPMC7863484 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Low expression of ZHX1 and ZHX2 impacts on the prognosis of chronic lymphocytic leukemia.

Maciel Natália Ioseph Gladistone NIG Filiú-Braga Luma Dayane Carvalho LDC Neves Francisco Assis Rocha FAR Rego Eduardo Magalhaes EM Lucena-Araujo Antonio Roberto AR Saldanha-Araujo Felipe F

Biomarker research 20210204 1

Experimental evidence points to the role of Zinc fingers and homeoboxes protein 1 and 2 (ZHX1 and ZHX2) in the development and progression of several types of cancer, including hematological malignancies. Here, we determined whether the altered expression of ZHX1 and ZHX2 has clinical implications in patients with CLL. Interestingly, CLL patients with low expression ZHX1 and ZHX2 presented higher WBC counts. Importantly, our data showed that CLL patients with cytogenetic alterations presented re ...[more]

PMID: 33541423

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Project description:BackgroundIGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis.MethodsThe co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by 'WGCNA' package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan-Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes.Results2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA.ConclusionsThe expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.

Dataset Information

Low expression of ZHX1 and ZHX2 impacts on the prognosis of chronic lymphocytic leukemia.

Publications

Low expression of ZHX1 and ZHX2 impacts on the prognosis of chronic lymphocytic leukemia.

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