CREB3L1 overexpression as a potential diagnostic marker of Philadelphia chromosome–negative myeloproliferative neoplasms

Abstract

Discrimination of Philadelphia‐negative myeloproliferative neoplasms (Ph‐MPNs) from reactive hypercytosis and myelofibrosis requires a constellation of testing including driver mutation analysis and bone marrow biopsies. We searched for a biomarker that can more easily distinguish Ph‐MPNs from reactive hypercytosis and myelofibrosis by using RNA‐seq analysis utilizing platelet‐rich plasma (PRP)‐derived RNAs from patients with essential thrombocythemia (ET) and reactive thrombocytosis, and CREB3L1 was found to have an extremely high impact in discriminating the two disorders. To validate and further explore the result, expression levels of CREB3L1 in PRP were quantified by reverse‐transcription quantitative PCR and compared among patients with ET, other Ph‐MPNs, chronic myeloid leukemia (CML), and reactive hypercytosis and myelofibrosis. A CREB3L1 expression cutoff value determined based on PRP of 18 healthy volunteers accurately discriminated 150 driver mutation–positive Ph‐MPNs from other entities (71 reactive hypercytosis and myelofibrosis, 6 CML, and 18 healthy volunteers) and showed both sensitivity and specificity of 1.0000. Importantly, CREB3L1 expression levels were significantly higher in ET compared with reactive thrombocytosis (P < .0001), and polycythemia vera compared with reactive erythrocytosis (P < .0001). Pathology‐affirmed triple‐negative ET (TN‐ET) patients were divided into a high– and low–CREB3L1‐expression group, and some patients in the low‐expression group achieved a spontaneous remission during the clinical course. In conclusion, CREB3L1 analysis has the potential to single‐handedly discriminate driver mutation–positive Ph‐MPNs from reactive hypercytosis and myelofibrosis, and also may identify a subgroup within TN‐ET showing distinct clinical features including spontaneous remission.

The Clinical Significance and Potential Molecular Mechanism of Upregulated CDC28 Protein Kinase Regulatory Subunit 1B in Osteosarcoma

“…Simultaneously, in proliferating osteoblastic OS, CREB3L1, ZNF460, and OSR2 were identified as the most active TFs. CREB3L1 is mainly distributed on the endoplasmic reticulum of osteoblasts and astrocytes [ 104 ]. Additionally, CREB3L1 is a key effector downstream of unfolded protein response (UPR) pathway and inhibits cell proliferation and induces apoptosis by binding cis acting elements of tumor suppressor genes [ 105 , 106 ].…”

“…Simultaneously, in proliferating osteoblastic OS, CREB3L1, ZNF460, and OSR2 were identified as the most active TFs. CREB3L1 is mainly distributed on the endoplasmic reticulum of osteoblasts and astrocytes [104].…”

Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms

“…Platelet samples were collected during patient's follow-up [15] and stored frozen at − 80 • C until use. For cell fraction CREB3L1 expression, platelets, red blood cells (RBCs), lymphocytes (Lym), and granulocytes (Gran) were isolated from 10 mL PB as follows: platelets were first isolated [15] with limited number of PB cells as determined by FACS (FACS Celesta, BD Biosciences) (Supplemental Fig.…”

“…CREB3L1 is expressed in the majority of solid tumors [11,12] and associated with metastasis in breast carcinoma [13,14]. The role of CREB3L1 in hematological diseases is still unknown; however, our group recently showed by RNA-sequencing analysis that CREB3L1 expression is significantly higher in platelets of patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), subgroups of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) [15] and that it is useful to discriminate reactive cases from neoplastic cases. Despite this, the biological significance of this overexpression and the clinical relevance of CREB3L1 in MPNs remains elusive.…”

Effects of endoplasmic reticulum stress‑mediated CREB3L1 on apoptosis of glioma cells

“…ERS is a necessary condition for the activation of CREB3L1, which is highly expressed in osteoblasts of bone tissue and astrocytes of the central nervous system (5). CREB3L1 has been indicated to be abnormally expressed in a variety of tumors and has an important role (6)(7)(8).…”