Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation.

Inflammatory and oncogenic signaling converge in disease evolution of BCR-ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34+ progenitor-enriched cultures from JAK2V617F+ PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients' bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFNγ- and NF-κB-associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes' expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1-inhibited parental JAK2V617F+ cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F+ PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis.

Hereditary red blood cell enzymopathies are genetic disorders affecting genes encoding red blood cell enzymes. They cause a specific type of anemia designated hereditary nonspherocytic hemolytic anemia (HNSHA). Enzymopathies affect cellular metabolism, which, in the red cell, mainly consists of anaerobic glycolysis, the hexose monophosphate shunt, glutathione metabolism, and nucleotide metabolism. Enzymopathies are commonly associated with normocytic normochromic hemolytic anemia. In contrast to other hereditary red cell disorders such as membrane disorders or hemoglobinopathies, the morphology of the red blood cell shows no specific abnormalities. Diagnosis is based on detection of reduced specific enzyme activity and molecular characterization of the defect on the DNA level. The most common enzyme disorders are deficiencies of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK). However, there are a number of other enzyme disorders, often much less known, causing HNSHA. These disorders are rare and often underdiagnosed, and the purpose of this review. In this brief review, we provide an overview of clinically relevant enzymes, their function in red cell metabolism, and key aspects of laboratory diagnosis.