1. Academic Validation
  2. CALR but Not JAK2 Mutations Are Associated with an Overexpression of Retinoid X Receptor Alpha in Essential Thrombocythemia

CALR but Not JAK2 Mutations Are Associated with an Overexpression of Retinoid X Receptor Alpha in Essential Thrombocythemia

  • Cancers (Basel). 2024 Apr 16;16(8):1511. doi: 10.3390/cancers16081511.
Ana Guijarro-Hernández 1 Cristina Hurtado 1 María José Larráyoz 2 María José Calasanz 2 José Luis Vizmanos 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain.
  • 2 CIMA LAB Diagnostics, Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain.
Abstract

Essential thrombocythemia (ET) is a blood Cancer caused by mutations in JAK2 and CALR. It is widely recognized that both mutations lead to the constitutive activation of JAK2/STAT signaling, although other JAK/STAT-independent pathogenic mechanisms triggered by these alterations have also been described in ET. In an attempt to study JAK2/STAT-independent mechanisms derived from CALR mutations, our research group created a C. elegans model with patient-like mutations in calreticulin that lacks JAK counterparts. The introduction of patient-like mutations in the calreticulin of C. elegans leads to an increase in the transcriptional expression of nhr-2, independently of JAK2/STAT activation. In the present study, we aim to verify if this mechanism is conserved in patients with ET harboring CALR mutations. To do so, we evaluated the expression of potential orthologs of nhr-2 in human cell lines of interest for the study, as well as in bone marrow (BM) or peripheral blood (PB) mononuclear cells from patients with CALR or JAK2 mutations. The results revealed that this mechanism is conserved in CALR-mutated ET patients, since CALR, but not JAK2 mutations, were associated with an overexpression of RXRA in patients with ET. The use of drugs targeting the activation or blockade of this target in the analyzed cell lines did not result in changes in cell viability. However, RXRA might be relevant in the disease, pointing to the need for future research testing retinoids and other drugs targeting RXRα for the treatment of ET patients.

Keywords

CALR; ET; RXRA; myeloproliferative neoplasms.

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