Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation

Abstract

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.

Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone

“…It encodes for the iron-binding nuclear protein pirin, a transcriptional regulator, and has been described as an oncogene [49] and promoter of metastatic tumor growth [50] on one hand and as a tumor suppressor gene on the other [51] in many solid cancers, but never before in glioma. In acute myeloid leukemia (AML), PIR was linked to terminal differentiation of myeloid precursors with a downregulation of PIR possibly related to the differentiation arrest observed in AML [52]. By contrast, overexpression of PIR was involved in inhibition of cellular senescence in melanocytic cells, resulting in transformation to melanoma [53].…”

Pirin Inhibits Cellular Senescence in Melanocytic Cells

“…We recently observed that PIR knockdown in hematopoietic precursors impairs terminal myeloid differentiation, and its down-regulation in leukemias may therefore contribute to the maturation arrest characteristic of acute myeloid leukemia. 31 The molecular mechanisms underlying the role of PIR in counteracting senescence remain unknown. PIR may contribute to this phenotype by modulating the transcription of key regulators of senescence, but it may also exert its function through other mechanisms.…”

Pirin is an iron-dependent redox regulator of NF-κB

“…In progenitor cells, the activation of pirin is an important event that alters the transcription profile of the cell to one that primes the cell for differentiation (38). Reduced pirin expression is a common feature of acute myelogenous leukemia, which results in the proliferation of immature myeloid cells.…”

“…Pirin has been proposed to be an important factor in cell differentiation (38). In progenitor cells, the activation of pirin is an important event that alters the transcription profile of the cell to one that primes the cell for differentiation (38).…”