Molecular pathophysiology of myelodysplastic syndromes

Abstract

The clinicopathologic heterogeneity of myelodysplastic syndromes (MDS) is driven by diverse, somatically acquired genetic abnormalities. Recent technological advances have enabled the identification of many new mutations, which have implicated novel pathways in MDS pathogenesis, including RNA splicing and epigenetic regulation of gene expression. Molecular abnormalities, either somatic point mutations or chromosomal lesions, can be identified in the vast majority of MDS cases and underlie specific disease phenotypes. As the full array of molecular abnormalities is characterized, genetic variables are likely to complement standard morphologic evaluation in future MDS classification schemes and risk models.

Figure 1. Somatic mutations in 255 cases of myelodysplastic syndrome with a normal karyotype or a −Y karyotype

Among cases with a normal karyotype or a −Y karyotype, 72% harbor somatic mutations in at least 1 of 17 genes tested. Each column represents one patient sample, and each row corresponds to mutations in a gene or gene family. TK pathway denotes mutations in genes that activate tyrosine kinase signaling (NRAS, KRAS, BRAF, CBL, and JAK2). Modified from Reference and based in part on Reference , with permission.

Figure 2. Mutations that affect RNA splicing machinery are common in myelodysplastic syndromes (MDS)

(a) Mutations in genes that encode components of the RNA splicing machinery are mutually exclusive and occur in a range of cytogenetic contexts. Each column represents one sample. Mutations are shown as red bars. Specific karyotypic abnormalities are color coded as follows: red, isolated deletion on the long arm of chromosome 5 [del(5q)]; green, −7/del(7q) alone or +1 abnormality; blue, isolated +8; yellow, isolated del(20q); black, complex; white, normal or −Y; orange, unknown. (b) Schematic of RNA splicing showing spliceosome-mediated precursor--messenger RNA processing that causes the excision of an intervening intron and ligation of flanking exons. (c) Selected components of the spliceosome are mutated in MDS. The U1 small nuclear ribonucleoprotein (snRNP) binds to the 5ʹ splice site (5ʹ SS), and the U2 snRNP binds to the branch point. The U2 auxiliary factor (U2AF), which is composed of U2AF1 and U2AF2 subunits, binds to the 3ʹ splice site (3ʹ SS) and polypyrimidine tract [Y_(n)]. Serine- and arginine-rich proteins bind to the exonic splice enhancer (ESE). The genes encoding SF3A1, SF3B1, U2AF1, U2AF2, SF1, SRSF2, and ZRSR2 are mutated in myeloid neoplasms and are shown in red. (d) Various outcomes of alternative splicing occur in normal physiology, including alternative splice-site selection, exon skipping, and intron retention.

Figure 3

(A) TET proteins successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), t-formylcytosine (5fC), and 5-carboxycytosine (5caC). (B) TET2 mutation (mTET2) results in reduced enzymatic activity and decreased products of 5mC oxidation.

Figure 4. TP53 mutations are associated with a complex karyotype and reduced overall survival

(a) A subset of 439 patients with myelodysplastic syndrome (MDS) (7), including those with TP53 mutation (n = 33) or a complex karyotype (n = 57). Each column represents one case, and mutations are represented as colored bars. Specific karyotypes are color coded as in Figure 2. (b) Survival of MDS patients with a complex karyotype, either with (n = 26; red line) or without (n = 31; blue line) TP53 mutations. Survival of MDS patients associated with a noncomplex karyotype and wild-type TP53 (n = 368) is represented as a gray line. TK pathway denotes mutations in genes that activate tyrosine kinase signaling. Modified from Reference with permission.