{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T18:18:58Z","timestamp":1775067538603,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Cancer Biology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL007971"],"award-info":[{"award-number":["HL007971"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL146722"],"award-info":[{"award-number":["HL146722"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL146373"],"award-info":[{"award-number":["HL146373"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NCI","award":["CA271523"],"award-info":[{"award-number":["CA271523"]}]},{"name":"NCI","award":["CA282668"],"award-info":[{"award-number":["CA282668"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITP\u03b2 is critical for the development of JAK2V617F-driven MPN in mice. Deleting\n                  <jats:italic>Pitp<\/jats:italic>\n                  \u03b2 across the hematopoietic system, but not\n                  <jats:italic>Pitp<\/jats:italic>\n                  \u03b1, prolonged 25-week survival of Jak2V617F mice from 10% to 85%. Loss of\n                  <jats:italic>Pitp<\/jats:italic>\n                  \u03b2 attenuated disease-associated splenomegaly and curtailed erythroid progenitors expansion both\n                  <jats:italic>in vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Mechanistically, PITP\u03b2 is necessary for AKT hyperactivation in hematopoietic progenitors, while STAT5 and ERK signaling remain unaffected. In alignment with this role, PITP\u03b2 promotes the production of PtdIns(3,4)P\n                  <jats:sub>\u2082<\/jats:sub>\n                  , a phosphoinositide that sustains aberrant AKT signaling in Jak2V617F progenitors. Pharmacologic inhibition of AKT with the FDA-approved inhibitor capivasertib in Jak2V617F-transplanted mice similarly reduced splenomegaly and erythroid proliferation, mimicking the effects of\n                  <jats:italic>Pitp<\/jats:italic>\n                  \u03b2 loss. Collectively, these results identify a novel PITP\u03b2-PtdIns(3,4)P\n                  <jats:sub>\u2082<\/jats:sub>\n                  signaling axis that selectively maintains pathological AKT activation in JAK2V617F-driven MPN, revealing a promising therapeutic vulnerability.\n                <\/jats:p>","DOI":"10.64898\/2026.03.26.714558","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:15:15Z","timestamp":1774898115000},"source":"Crossref","is-referenced-by-count":0,"title":["PITP\u03b2 Drives JAK2 V617F-Mediated Myeloproliferative Neoplasms by Promoting PtdIns(3,4)P\n                  <sub>\u2082<\/sub>\n                  -Dependent AKT Hyperactivation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2199-6452","authenticated-orcid":false,"given":"Nikita A.","family":"Vantsev","sequence":"first","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Morioka","sequence":"additional","affiliation":[{"name":"Department of Lipid Biology, Graduate School of Medical & Dental Sciences Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Kajiho","sequence":"additional","affiliation":[{"name":"Department of Lipid Biology, Graduate School of Medical & Dental Sciences Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Lipid Biology, Graduate School of Medical & Dental Sciences Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Lipid Biology, Graduate School of Medical & Dental Sciences Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles S.","family":"Abrams","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9951-2273","authenticated-orcid":false,"given":"Wei","family":"Tong","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040109401874000_2026.03.26.714558v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)71142-9"},{"key":"2026040109401874000_2026.03.26.714558v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03546"},{"key":"2026040109401874000_2026.03.26.714558v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051113"},{"key":"2026040109401874000_2026.03.26.714558v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.03.023"},{"key":"2026040109401874000_2026.03.26.714558v1.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110556"},{"key":"2026040109401874000_2026.03.26.714558v1.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-485888"},{"key":"2026040109401874000_2026.03.26.714558v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.05.015"},{"key":"2026040109401874000_2026.03.26.714558v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(69)90063-7"},{"key":"2026040109401874000_2026.03.26.714558v1.9","first-page":"6382","article-title":"Phospholipid exchange between membranes. 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