The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia

Abstract

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

“…Since dysregulated innate immune and inflammatory signaling is observed in preleukemic states, it is viewed as an early alteration, while second-hit mutations, such as in RUNX1, RAS, or FLT3, are associated with malignant transformation. 2 Therefore, to model the progression from preleukemic states to overt AML, we introduced a dominant-negative RUNX1 frameshift mutant (S291fsX300, herein RUNX1 mut ) into miR-146a knockout (KO) HSPCs. 25 This mutation results in the C-terminal truncation of the wild-type RUNX1 protein, which still retains DNA binding activity, but it is unable to recruit co-activators/repressors due to the lack of the transactivation domain.…”

“… 1 The transition from MDS to AML typically involves the acquisition of mutations in genes like RUNX1, NRAS/KRAS, or FLT3. 2 However, the preleukemic molecular and cellular states that are amenable to transformation to overt AML are not entirely understood. In preleukemic conditions, there is a notable presence of cell-intrinsic innate immune signaling within mutant HSPCs.…”

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

“…29,30 In MDS, genetic landscape differs between low-and high-risk MDS and between those myelodysplasias that rapidly progress to AML. 29,31,32 Accumulation of epigenetic modifications together with occurrence of TET2, IDH1, and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML. 7,29,33 Most frequent mutations involve SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, ZRSR2, STAG2, TP53, EZH2, CBL, JAK2, BCOR, IDH2, NRAS, and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities.…”

“…35 NRAS, ASXL1, RUNX1, and SETBP1 gene mutations are mutated only in less than 10% of MDS cases, even though are independent risk factors for inferior survival and the increased risk to AML transformation. 32,36 SETBP1, a 170-kDa nuclear protein that binds to SET protein, to AT-rich DNA regions-"AAAATAA/T" sequences, to promoter regions of genes involved in hemopoiesis, such as HOXA9, HOXA10, and RUNX1, 31,[37][38][39][40] to members of the KMT2A (lysine methyltransferase)-COMPASS (COMplex of Proteins ASsociated with SET1) family ultimately leading to methylation regulation of promoter regions of the HOX genes, 37 or to modified histones. 41,42 SETBP1 somatic mutations can occur in MDS and AML, causing upregulation of several genes, such as MECOM, a transcriptional regulator and oncoprotein involved in hematopoiesis, apoptosis, development, and cell differentiation and proliferation.…”

“…In primary AML, NPM1 , DNMT3A , FLT3 ‐ITD, NRAS / KRAS , CEBPA dm , KIT , IDH1/2 , PTPN11 , WT1 , and RAD21 are frequently mutated, with slight differences in elderly with TET2 (42%), DNMT3A (35%), NPM1 (32%), SRSF2 (25%), and ASXL1 (21%) mostly mutated 29,30 . In MDS, genetic landscape differs between low‐ and high‐risk MDS and between those myelodysplasias that rapidly progress to AML 29,31,32 . Accumulation of epigenetic modifications together with occurrence of TET2 , IDH1 , and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML 7,29,33 .…”