TY - JOUR
T1 - In Vivo Monitoring of Polycythemia Vera Development Reveals Carbonic Anhydrase 1 as a Potent Therapeutic Target
AU - Murakami, Shohei
AU - Barroca, Vilma
AU - Perié, Leïla
AU - Bravard, Anne
AU - Bernardino-Sgherri, Jacqueline
AU - Tisserand, Amandine
AU - Devanand, Caroline
AU - Edmond, Valérie
AU - Magniez, Aurélie
AU - Bento, Sabrina Tenreira
AU - Torres, Claire
AU - Pasquier, Florence
AU - Plo, Isabelle
AU - Vainchenker, William
AU - Villeval, Jean Luc
AU - Roméo, Paul Henri
AU - Lewandowski, Daniel
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Current murine models of myeloproliferative neoplasms (MPNs) cannot examine how MPNs progress from a single bone marrow source to the entire hematopoietic system. Thus, using transplantation of knock-in JAK2V617F hematopoietic cells into a single irradiated leg, we show development of polycythemia vera (PV) from a single anatomic site in immunocompetent mice. Barcode experiments reveal that grafted JAK2V617F stem/progenitor cells migrate from the irradiated leg to nonirradiated organs such as the contralateral leg and spleen, which is strictly required for development of PV. Mutant cells colonizing the nonirradiated leg efficiently induce PV in nonconditioned recipient mice and contain JAK2V617F hematopoietic stem/progenitor cells that express high levels of carbonic anhydrase 1 (CA1), a peculiar feature also found in CD34+ cells from patients with PV. Finally, genetic and pharmacologic inhibition of CA1 efficiently suppresses PV development and progression in mice and decreases PV patients’ erythroid progenitors, strengthening CA1 as a potent therapeutic target for PV.
AB - Current murine models of myeloproliferative neoplasms (MPNs) cannot examine how MPNs progress from a single bone marrow source to the entire hematopoietic system. Thus, using transplantation of knock-in JAK2V617F hematopoietic cells into a single irradiated leg, we show development of polycythemia vera (PV) from a single anatomic site in immunocompetent mice. Barcode experiments reveal that grafted JAK2V617F stem/progenitor cells migrate from the irradiated leg to nonirradiated organs such as the contralateral leg and spleen, which is strictly required for development of PV. Mutant cells colonizing the nonirradiated leg efficiently induce PV in nonconditioned recipient mice and contain JAK2V617F hematopoietic stem/progenitor cells that express high levels of carbonic anhydrase 1 (CA1), a peculiar feature also found in CD34+ cells from patients with PV. Finally, genetic and pharmacologic inhibition of CA1 efficiently suppresses PV development and progression in mice and decreases PV patients’ erythroid progenitors, strengthening CA1 as a potent therapeutic target for PV.
UR - http://www.scopus.com/inward/record.url?scp=85160032090&partnerID=8YFLogxK
U2 - 10.1158/2643-3230.BCD-21-0039
DO - 10.1158/2643-3230.BCD-21-0039
M3 - Article
AN - SCOPUS:85160032090
SN - 2643-3230
VL - 3
SP - 285
EP - 297
JO - Blood Cancer Discovery
JF - Blood Cancer Discovery
IS - 4
ER -