Expression of different functional isoforms in haematopoiesis

Abstract

Haematopoiesis is a complex process regulated at various levels facilitating rapid responses to external factors including stress, modulation of lineage commitment and terminal differentiation of progenitors. Although the transcription program determines the RNA pool of a cell, various mRNA strands can be obtained from the same template, giving rise to multiple protein isoforms. The majority of variants and isoforms co-occur in normal haematopoietic cells or are differentially expressed at various maturity stages of progenitor maturation and cellular differentiation within the same lineage or across lineages. Genetic aberrations or specific cellular states result in the predominant expression of abnormal isoforms leading to deregulation and disease. The presence of upstream open reading frames (uORF) in 5' untranslated regions (UTRs) of a transcript, couples the utilization of start codons with the cellular status and availability of translation initiation factors (eIFs). In addition, tissue-specific and cell lineage-specific alternative promoter use, regulates several transcription factors producing transcript variants with variable 5' exons. In this review, we propose to give a detailed account of the differential isoform formation, causing haematological malignancies.

Distinct transcriptomic and exomic abnormalities within myelodysplastic syndrome marrow cells

“…RNA and protein isoforms play an important role in determining gene function in hematopoiesis and may influence disease outcome in MDS and AML. [20,53] Alternative splicing (predominantly) and modulation of transcriptional activity regulate spatio-temporal isoform expression. [54–56] The genes that modulate these mechanisms are frequently mutated or have altered function in MDS[54].…”

“…Distinct isoforms have specific roles in hematopoietic lineage generation. [20] The mechanisms for RNA isoform selection, i.e., alternative splicing and transcriptional start site usage, are often dysfunctional in diseases such as MDS and AML where aberrant isoform expression has been reported. [21,22] In this study we have additionally evaluated the differential isoforms usage within the transcriptomes of our MDS patient cohort.…”

Aberrant splicing and drug resistance in AML

“…There are two well-known protein families of RNA-binding splice factors: the serine-rich (SR) proteins that typically promote exon inclusion and the heterogenous nuclear ribonucleoproteins (hnRNP) that generally promote exon skipping [ 7 ]. Alternative splicing is an important part of normal hematopoiesis and is necessary for cellular differentiation and rapid responses to external stimuli [ 8 ]. However, imbalances in the splicing machinery can trigger abnormal programs associated with malignancies such as myelodysplastic syndromes (MDS) and AML [ 9 ].…”

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

“…The cellular components of blood are formed from a pool of stem cells in the bone marrow, through an organized pathway called the hematopoietic system (Grech et al, 2014). The pluripotent stem cells are capable of differentiation to form any of the elements of blood, but overproliferation by these cells can lead to a condition called blood cancer or leukemia (Prasanthi et al, 2010;Li et al, 2012).…”