Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

Abstract

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS.

Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design

“…For example, SureSeq™ panels were designed for analysis of AML and MPN cases, but it lacked essential genes for the study of MDS, such as genes involved in splicing (SF3B1, SRSF2, ZRSR2), epigenetic regulation (EZH2), transcriptional regulation (GATA2) or signal transduction (CBL) [22][23] [24] [25]. Similarly, MYS panel was designed to characterize the mutational landscape of MDS, MPN and AML, but it missed a number of relevant genes such as the transcription regulators GATA2, IKZF1, and PHF6 [25] [26]. On the contrary, TSMP included some genes relevant to lymphoid malignancies, such as MYD88, NOTCH1 and PTEN [27][28] [29].…”

Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era

“…Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) are important subsets of secondary malignancies. MDS is a group of haematopoietic stem cell disorders, characterized by ineffective haematopoiesis that leads to cytopenia, and carries a major risk of transforming into AML (Gill et al, 2016). The incidence of therapy-related MDS/AML has increased in recent years, with 10-20% of MDS cases being therapy-related (Candelaria & Duenas-Gonzalez, 2015;Yang et al, 2015).…”

Does SF3B1/TET2 Double Mutation Portend Better or Worse Prognosis Than Isolated SF3B1 or TET2 Mutation?

“…Risk stratification of myeloid neoplasms based on a prognostic scoring system determines the therapeutic approach. The treatment of low-risk patients is conservative, while the treatment of high-risk MDS involves the use of hypomethylating agents and allogeneic hematopoietic stem cell transplantation in younger patients (21). However, gene mutations are playing increasingly more important roles in risk stratification and therapeutic decision making in myeloid neoplasms.…”