Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40-60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

Keywords: hypomethylating agents; immunotherapy; myelodysplastic syndromes; targeted therapy; treatment resistance.

Figure 1

Molecular pathogenesis of MDS. Signal transduction molecules refer to gene mutations resulting in alteration to proliferative or apoptotic effects. Transcription factors and epigenetic regulators exert effects at both transcriptional and translational levels due to aberrations in RNA splicing, DNA methylation, and histone modification.

Figure 2

Driver mutations in splicing factors. The diagram shows key driver mutations in splicing factors in myelodysplastic syndrome and their potential splicing outcomes if one or more of these splicing factors are mutated.

Figure 3

Mechanisms of DNA methylation under epigenetic dysregulation in MDS. Under normal circumstances, IDH1/2 promotes the TET2 genes to perform the conversion of 5-mC to 5-hMC, triggering DNA methylation. However, IDH1/2 mutations are often seen in MDS causing the inhibition of TET2, resulting in global hypomethylation but loci-specific hypermethylation.

Figure 4

Mechanism of histone modification in MDS. Under normal circumstances, the PRC2 complex promotes methylation by regulating H3K27me resulting in transcriptional activation. However, loss-of-function mutation of EZH2 causes PCR2 to malfunction resulting in HSC disorders.

Figure 5

Schematic representation of AZA and DEC uptake and metabolism. UCK—uridine-cytidine kinase, DCK—deoxycytidine kinase, CDA—cytidine deaminase, NMPK—nucleoside monophosphate kinase, NDPK—nucleoside diphosphatase kinase, RNR—ribonucleotide reductase.