The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

Abstract

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

Figure 1. Recurrent mutations in CHIP and MDS

Mutations are sorted by their frequency in MDS within functional categories. Mutation percentages (%) shown for all categories except CHIP, where the absolute mutation count is shown (#). CHIP: Clonal hematopoiesis of indeterminate potential^,. MDS: Myelodysplastic syndrome^,,,. AML: Acute myeloid leukemia^–. sAML: Secondary acute myeloid leukemia. AA: Aplastic anemia. AlloHSCT, allogeneic hematopoietic stem cell transplantation; HMAs, hypomethylating agents; MonoMAC, monocytosis with increased susceptibility to mycobacterial infections; MPN: Myeloproliferative neoplasm. CMML: Chronic myelomonocytic leukemia. JMML: Juvenile myelomonocytic leukemia.

Figure 2. Clonal expansion in MDS

Early mutations tend to lead to increased hematopoietic stem cell (HSC) self-renewal, clonal expansion and the development of clonal hematopoiesis of indeterminate potential (CHIP). As the mutant clone continues to enlarge, it gives rise to an expanding population of cells in which acquisition of additional genetic or epigenetic lesions can promote progression to overt malignancy. These secondary subclonal events tend to lead to the development of overt dysplasia, myelodysplastic syndrome (MDS) and eventually secondary acute myeloid leukemia (sAML).

Figure 3. Splicing factor mutations in myeloid neoplasms

Shown is a simplified schematic of the steps involved in mRNA splicing. Splicing factor mutations cluster within components of the 3′ spliceosome. Genes mutated in MDS are denoted in red. YYY: Polypyrimidine tract. A: Branch site. AG: Splice acceptor site. ESE: Exonic splicing enhancer. SF1, splicing factor 1; SF3B1, splicing factor 3b subunit 1; SRSF2, serine and arginine rich splicing factor 2; U2AF1, U2 small nuclear RNA auxiliary factor 1; ZRSR2, zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2. Modified with permission from Boultwood et al.

Figure 4. Multiple steps in gene expression are recurrently disrupted in MDS

Shown is a prototypical gene promoter with chromosomal looping facilitated by CCCTC-binding factor (CTCF) and the cohesin complex, allowing transcription factors (TFs) bound at distant enhancers to interact with the promoter. Alterations in epigenetic marks such as DNA methylation and histone post-translational modifications function to regulate the transcription of genes. Green signifies loss of function (or dominant negative function) mutations. Red signifies gain of function mutations. C, cytosine; 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethyl-cytosine; H2AK119Ub, histone H2A lysine 119 ubiquitylation; H3K27, histone H3 lysine 27; H3K27me3, H3K27 trimethylation; IDH, isocitrate dehydrogenase; DNMT3A, DNA methyltransferase 3A; TET2, ten-eleven translocation 2; EZH2, enhancer of zeste 2; BCOR, BCL6 corepressor; ASXL1, additional sex combs-like 1; RUNX1, runt related transcription factor 1; ETV6, ETS variant 6; WT1, Wilms tumor 1; SMC1A, structural maintenance of chromosomes 1A; STAG2, stromal antigen 2.

Figure 5. Mechanism of lenalidomide efficacy in 5q⁻ syndrome

(A) Lenalidomide (LEN) functions through modulation of the substrate binding specificity of cereblon (CRBN), a component of an E3 ubiquitin ligase, for casein kinase 1α (CK1α, encoded by CSNK1A1). In the absence of LEN, CRBN has low affinity for CK1α. Binding of LEN, however, induces a conformational change in CRBN that significantly increases this affinity, thereby catalyzing efficient ubquitination and degradation of CK1α. . (B) Hematopoietic stem cells (HSCs) harboring 5q deletion (5q⁻ syndrome), which lack one copy of CSNK1A1 and have a lower CK1α level have a clonal advantage over wildtype cells at baseline. Treatment with LEN selectively depletes CK1α in all HSCs; in 5q⁻ cells this pushes the CK1α level below a critical threshold and triggers cell death, whereas wildtype CSNK1A1 cells retain enough CK1α for survival and can eventually repopulate the bone marrow.