Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients

Abstract

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are divided in three major groups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 WHO classification incorporates also prefibrotic PMF (pre-PMF) and overt PMF. This study aimed to discriminate the clinical features, genetic alterations, and outcomes in patients with prefibrotic, overt PMF, and secondary MF (SMF). This study included 229 patients with diagnosed myelofibrosis (MF). Among 229 patients, 67 (29%), 122 (53%), and 40 (18%) were confirmed as SMF, overt PMF, and pre-PMF, respectively. The JAK2 V617F mutation was differentially distributed in SMF and PMF, contradictory to CALR and MPL mutations. Regarding nondriver mutations, the occurrence of ASXL1 mutations differed between PMF and SMF or pre-PMF. The three-year overall survival was 91.5%, 85.3%, and 94.8% in SMF, overt PMF, and pre-PMF groups. Various scoring systems could discriminate the overall survival in PMF but not in SMF and pre-PMF. Still, clinical features including anemia and thrombocytopenia were poor prognostic factors throughout the myelofibrosis, whereas mutations contributed differently. Molecular grouping by wild-type SF3B1 and SRSF2/RUNX1/U2AF1/ASXL1/TP53 mutations showed inferior progression-free survival (PFS) in PMF, SMF, and pre-PMF. We determined the clinical and genetic features related to poor prognosis in myelofibrosis.

Non-driver mutations landscape in different stages of primary myelofibrosis determined ASXL1 mutations play a critical role in disease progression

“…5). The frequency of ASXL1 mutations gradually increased from Pre-PMF to PMF-AP/BP (10.1-51.1%), consistent with two other studies for Asian PMF patients [21,23] . Moreover, ASXL1 mutations were signi cantly associated with both Overt-PMF and PMF-AP/BP, while U2AF1 mutations as well as RUNX1 and NRAS mutations were only associated with Overt-PMF or PMF-AP/BP, respectively.…”

“…ASXL1 mutations have been identi ed as the most frequent non-driver mutation in PMF (21.7%∼36.1%) [8,21−24] and as the rst genetic lesions, preceding driver mutations [25] . Moreover, the frequency of ASXL1 mutations is much higher in post-PV/ET MF (28.4%∼41.2%) [12,15,23] than in PV(10%∼12%) [26][27] and ET (3%1∼1%) [21,26−27] . From clinical data, it seems that ASXL1 mutations associate with more severe subtypes of MPN.…”

The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases

“…The phosphorylation (elevated Ca 2+ and AMP levels) or deacetylation (sirtuin 1 [SIRT1]) of PGC-1α leads to its activation, following which it binds to nuclear respiratory factor 1 and 2 (NRF-1 and NRF-2), leading to the expression of a wide range of mitochondrial genes, including mitochondrial transcription factor A (TFAM) [74,75]. The treatment of dopaminergic (DA) neurons or SH-SY5Y cells with SNOC, a NO donor, was shown to induce Parkin-interacting substrate (PARIS), which contributed to PGC-1α nuclear translocation; this resulted in a reduction in mitochondrial DNA copy number and ATP concentrations, leading to mitochondrial dysfunction [76]. The nuclear SNO of p53 at cysteine C124 promotes the binding of p53 to the −2317 p53RE on the promoter of the mouse Ppargc1a gene (encoding PGC-1α), inducing its transcription.…”

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression

“…ET and prePMF are each characterized by thrombocytosis and are difficult to distinguish by clinical and histopathological criteria. ET and prePMF also share overlapping cytogenetic abnormalities with other Ph-MPNs, including a gain of chromosome 1q, trisomy of chromosomes 8 and 9, as well as del(13q) and del(20q) [2,3]. While chromosomal abnormalities are detected in 50% of patients with PMF and in ~30% with PV, they are relatively rare in the context of ET with an incidence of <10%.…”