{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:04:46Z","timestamp":1790787886293,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Colony Stimulating Factor 3 Receptor (CSF3R) mutations are the molecular hallmark of chronic neutrophilic leukemia (CNL). A subset of these patients (~25%) have two mutations in CSF3R on the same allele. These \"compound\" CSF3R mutations include both an activating point mutation and a cytoplasmic truncating mutation. While compound mutations are prevalent, we have a limited understanding of their molecular characteristics. In this study, we interrogated the mechanisms driving the evolution of compound mutations. We found that CSF3R compound mutations induce a hyperproliferative leukemia compared to single mutations. Compound mutations also markedly enhance activation of STAT5 and ERK1\/2 downstream of CSF3R. Utilizing a proteomics approach, we identified enrichment of MYC and mTOR pathways in compound mutant-cells. The most differentially expressed protein in this dataset was the kinase PIM1. We find that in CSF3R compound mutant-cells with high STAT activity there is increased transcription of PIM kinases. We further validated that PIM1 transcript levels are high in a human CSF3R mutant-cohort. High PIM levels drive stabilization of MYC protein, and the downstream activation of MYC-driven leukemogenic transcriptional programs. Indeed, inhibitors of PIM reverse MYC stabilization. Finally, we show promising therapeutic potential for PIM-inhibition in CSF3R mutant-disease using both human cell lines and CNL patient samples. Together, these findings uncover a novel and targetable vulnerability in CSF3R compound mutant-CNL, thus opening a new avenue of treatment for patients with this devastating disease.<\/jats:p>","DOI":"10.1182\/blood.2026034085","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:45:16Z","timestamp":1790786716000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["CSF3R compound mutations produce a hyperproliferative leukemia driven by overexpression of PIM kinases"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-7423","authenticated-orcid":false,"given":"Breanna N","family":"Maniaci","sequence":"first","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7675-1777","authenticated-orcid":false,"given":"Jacob Edward","family":"Porter","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqian L","family":"Carlson","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4591-6007","authenticated-orcid":false,"given":"Grace","family":"Potter","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8988-4003","authenticated-orcid":false,"given":"Thai T","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2347-6656","authenticated-orcid":false,"given":"Amara","family":"Pang","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey W","family":"Tyner","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University School of Medicine, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Emili","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore P","family":"Braun","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia E","family":"Maxson","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, Oregon, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,9]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026034085\/2588229\/blood.2026034085.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026034085\/2588229\/blood.2026034085.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:45:16Z","timestamp":1790786716000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026034085\/570869\/CSF3R-compound-mutations-produce-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026034085","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"article-number":"blood.2026034085"}}