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Updated: Jun 4, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Polymorphisms within genes encoding Ikaros family proteins IKZF1 and IKZF3 in multiple myeloma patients treated with
Piotr Łacina1, Diana Porzuczek2, Katarzyna Bogunia-Kubik1
1Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
Background:
Multiple myeloma (MM) is a hematological malignancy characterized by the presence of abnormal plasma cells. It is associated with anemia, bone lesions and renal dysfunction. Immunomodulatory drugs (IMiDs) are commonly used in MM treatment. Recent studies indicate that their therapeutic effect is caused by binding to cereblon (CRBN), which in turn causes the degradation of 2 important immune cell regulatory factors, IKZF1 and IKZF3. These are necessary for the anti-myeloma effect of IMiDs. Their expression level has been shown to affect MM survival and response to treatment. Potentially important single-nucleotide polymorphisms (SNPs) in the genes coding for IKZF1 and IKZF3 have been identified, but they have not been analyzed in MM patients before.
Objectives:
The study was designed to establish the relationship between 4 SNPs in the genes coding for IKZF1 (rs61731359, rs4132601 and rs10272724) and IKZF3 (rs907091), and MM survival, response to treatment and other parameters.
Material And Methods:
The study involved 222 MM patients, as well as 100 control individuals. The IKZF1 and IKZF3 genotypes were determined by the LightSNiP assay. Genotyping was performed in the real-time polymerase chain reaction (PCR) LightCycler 480 device.
Results:
No difference was observed between the patients and the controls for any of the SNPs, but the IKZF1 and IKZF3 variants were associated with various clinical parameters. Allele IKZF1 rs4132601 G was more common in the patients with worse response to first-line therapy (p = 0.040), particularly in the patients treated with thalidomide (p = 0.017). The patients tended to have worse overall survival. IKZF3 rs907091 CC was detected more commonly in the patients in stage I than in those in stages II and III, according to the International Staging System (ISS) criteria (p = 0.015). This genotype was also associated with a higher albumin level (p = 0.033), and was less common in the patients with the albumin level below 3.5 g/dL (p = 0.030).
Conclusions:
Our results suggest that IKZF1 rs4132601 and IKZF3 rs907091 may affect response to treatment and progression in patients with MM.
Insights
Genetic variations in IKZF1 and IKZF3 influence multiple myeloma treatment response and survival. Specific single-nucleotide polymorphisms (SNPs) like IKZF1 rs4132601 and IKZF3 rs907091 are linked to patient outcomes.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Multiple myeloma (MM) is a plasma cell malignancy.
- Immunomodulatory drugs (IMiDs) treat MM by targeting cereblon (CRBN), leading to IKZF1 and IKZF3 degradation.
- IKZF1 and IKZF3 expression impacts MM survival and treatment response.
Purpose of the Study:
- To investigate the association between four single-nucleotide polymorphisms (SNPs) in IKZF1 and IKZF3 genes and multiple myeloma (MM) patient outcomes.
- To analyze the relationship between specific SNPs (IKZF1: rs61731359, rs4132601, rs10272724; IKZF3: rs907091) and MM survival, treatment response, and clinical parameters.
Main Methods:
- Genotyping of 222 MM patients and 100 controls using the LightSNiP assay on a LightCycler 480 real-time PCR system.
- Analysis of four specific SNPs in the IKZF1 and IKZF3 genes.
Main Results:
- No significant differences in SNP frequency were observed between MM patients and controls.
- The IKZF1 rs4132601 G allele was associated with poorer response to first-line therapy, especially with thalidomide, and tended towards worse overall survival.
- The IKZF3 rs907091 CC genotype was more frequent in early-stage MM patients (ISS Stage I) and correlated with higher albumin levels.
Conclusions:
- IKZF1 rs4132601 and IKZF3 rs907091 genotypes may serve as predictive markers for treatment response and disease progression in multiple myeloma patients.
- These findings highlight the potential role of specific genetic variants in influencing MM clinical outcomes.
