What process is most likely defective in chronic lymphocytic leukemia (CLL) cells with mutations in the gene encoding U1 small nuclear ribonucleic acid (snRNA)?

The Role of U1 snRNA Mutations in Chronic Lymphocytic Leukemia

The most likely defective process in chronic lymphocytic leukemia cells with mutations in the gene encoding U1 snRNA is the removal of introns from pre-mRNA (option E), as U1 snRNA plays a critical role in pre-mRNA splicing.

Understanding U1 snRNA Function in Splicing

U1 small nuclear RNA (snRNA) is a core component of the spliceosome, which is responsible for removing introns from pre-mRNA transcripts. When examining the molecular pathogenesis of chronic lymphocytic leukemia (CLL), mutations affecting splicing machinery have emerged as significant drivers of disease progression.

Molecular Evidence Supporting Splicing Defects in CLL

Recent research has identified SF3B1 as the second most frequently mutated gene in CLL (occurring in approximately 15% of patients), which functions at the catalytic core of the spliceosome 1. Importantly, studies have demonstrated that tumor samples with mutations in splicing factors like SF3B1 show alterations in pre-mRNA splicing, highlighting the critical role of this cellular process in CLL pathogenesis 1.

Genetic Abnormalities in CLL

CLL is characterized by various genetic abnormalities that contribute to its heterogeneous clinical behavior:

• The most common genetic abnormalities in CLL include:

  • Deletions of 13q (55%)
  • Deletions of 11q (6-20%)
  • Deletions of 17p/TP53 mutations (5-8% in treatment-naïve patients)
  • Trisomy 12 (11-25%)
  • Mutations in splicing factors (particularly SF3B1)

• TP53 disruption is considered the strongest predictor of resistance to chemoimmunotherapy 2

Clinical Implications of Splicing Defects

Mutations affecting splicing machinery components like U1 snRNA have significant clinical implications:

• Patients with splicing factor mutations often show distinct transcriptional profiles
• SF3B1 mutations frequently occur in tumors with deletions in chromosome 11q, which are associated with poor prognosis 1
• Transcriptome sequencing has revealed that thousands of genes exhibit CLL-specific splicing patterns, even when not differentially expressed at the gene level 3

Why Other Options Are Less Likely

1. Addition of CCA to the 3' end of tRNAs - This process is not prominently implicated in CLL pathogenesis based on current evidence.

2. Assembly of mature ribosomes - While ribosomal pathways may be downregulated in CLL 3, direct mutations affecting ribosome assembly are not a hallmark of CLL.

3. Recognition of the correct AUG by the 40S ribosomal subunit - Translation initiation defects have not been specifically linked to U1 snRNA mutations in CLL.

4. Recognition of the 5' end of group III introns - Group III introns are not found in human cells; they are primarily found in organellar genes of certain eukaryotes.

5. Removal of the 5' end of tRNAs - tRNA processing abnormalities have not been established as a key mechanism in CLL pathogenesis.

Clinical Relevance of Understanding Splicing Defects in CLL

Understanding the role of splicing defects in CLL has important implications for:

• Risk stratification - Splicing factor mutations may help identify high-risk patients
• Treatment selection - Patients with splicing machinery defects may respond differently to targeted therapies
• Development of novel therapeutic approaches targeting splicing abnormalities

The European Research Initiative on CLL (ERIC) recommends comprehensive genetic analysis for CLL patients, which should include assessment of splicing factor mutations alongside established markers like TP53 status and IGHV mutational status 2.