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一个独特的替代mRNA拼接配置文件识别了KMT2A重新排列的儿科T细胞急性淋巴细胞白血病细胞中的致癌CD44转录变体3

Amanda Ramilo Amor¹, Sabina Enlund¹, Indranil Sinha²

¹Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Experimental hematology

|January 10, 2025

概括

儿童T细胞急性淋巴细胞白血病 (T-ALL) 与KMT2A重组显示出不同的基因和拼接变异模式. CD44v3的上调表明,T-ALL.的风险分层是一个潜在的治疗标.

科学领域:

儿科瘤学儿科瘤学
分子生物学分子生物学
癌症遗传学癌症遗传学

背景情况:

在儿童ALL病例中,T细胞急性淋巴细胞白血病 (T-ALL) 占10-15%.
复杂的遗传异常,特别是KMT2A基因重组,与T-ALL.的预后不佳有关.
目前的治疗方法达到很高的治愈率,但确定预后标志物仍然至关重要.

研究的目的:

调查KMT2A重新排列 (KMT2A-r) 和KMT2A野生型 (KMT2A-wt) 儿科T-ALL之间的基因和拼接变体表达的差异.
为了确定KMT2A-r T-ALL.中风险分层的潜在分子标志物.
探索儿童T-ALL的新型治疗点.

主要方法:

在171个儿科T-ALL样本中对基因和拼接变异模式的比较分析.
对基因表达的定量分析,包括拼接调节标记.
对 CD44.4 的促进物甲基化和转录变异表达的分析.

主要成果:

在KMT2A-r T-ALL.中发现了明显的基因表达和拼接变体模式.
在KMT2A-r样本中观察到拼接调节标记ESRP1和MBNL3的显著上调.
在KMT2A-r T-ALL中,长期存活的BCL2长转录变异和瘤性CD44v3转录变异被上调,与增加的CD44促进体甲基化相关.

结论:

在KMT2A-r T-ALL中CD44v3上调可以作为基因表达基因风险分层标记.
CD44v3代表了KMT2A-r T-ALL的潜在治疗标,可能可以用拼接调节器治疗.

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RNA Splicing

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...

Alternative RNA Splicing

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...