Examining disease boundaries: Genetics of myelodysplastic/myeloproliferative neoplasms

Abstract

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid malignancies that are characterized by dysplasia resulting in cytopenias as well as proliferative features such as thrombocytosis or splenomegaly. Recent studies have better defined the genetics underlying this diverse group of disorders. Trisomy 8, monosomy 7, and loss of Y chromosome are the most common cytogenetic abnormalities seen. Chronic myelomonocytic leukemia (CMML) likely develops from early clones with TET2 mutations that drive granulomonocytic differentiation. Mutations in SRSF2 are common and those in the RAS‐MAPK pathway are typically implicated in disease with a proliferative phenotype. Several prognostic systems have incorporated genetic features, with ASXL1 most consistently demonstrating worse prognosis. Atypical chronic myeloid leukemia (aCML) is most known for granulocytosis with marked dysplasia and often harbors ASXL1 mutations, but SETBP1 and ETNK1 are more specific to this disease. MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) most commonly involves spliceosome mutations (namely SF3B1) and mutations in the JAK‐STAT pathway. Finally, MDS/MPN‐unclassifiable (MDS/MPN‐U) is least characterized but a significant fraction carries mutations in TP53. The remaining patients have clinical and/or genetic features similar to the other MDS/MPNs, suggesting there is room to better characterize this entity. Evolution from age‐related clonal hematopoiesis to MDS/MPN likely depends on the order of mutation acquisition and interactions between various biologic factors. Genetics will continue to play a critical role in our understanding of these illnesses and advancing patient care.

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

“…In addition to the frequent loss of SGK2, L3MBTL1, and other genes as part of the 20q deletion, this region also includes the non-imprinted epigenetic regulator ASXL1 gene at 20q11.21. ASXL1 is frequently mutated in hematological malignancies, and its mutations have been associated with drug resistance, inferior response to treatment, and poor prognosis of patients with leukemia or MDS [158][159][160][169][170][171]. The presence of ASXL1 mutations was associated with increased expression of PEAR1, a biomarker of inferior patient survival in the expanded Beat AML 2.0 cohort [101].…”

“…S4). The actively expressed, paternally inherited copies of both genes are commonly deleted in myeloproliferative neoplasms, which has been suggested to contribute to epigenetic dysregulation of chromatin function; in some cases, both genes are lost as part of larger areas, or the entire long arm of 20q is deleted, which is a frequent event in hematologic neoplasms [72,134,[157][158][159][160][161]. In the CCLE-GDSC dataset, each of these two genes had 1-7 copies across all cancer categories.…”

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

“…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.…”

The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia

“…NRAS and also ASXL1 , RUNX1 , and SETBP1 gene mutations were proved to be independent risk factors for inferior OS and the increased risk of MDS progression to leukemia [ 81 ].…”