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Using an in vitro model with proliferative stimuli of the in vivo lymph node niche (LN)\u2014including interleukin\u201021 (IL\u201021)\u2014we examined metabolic rewiring in chronic lymphocytic leukemia (CLL) cells. We found that the metabolic intermediates of upper glycolysis and its branching pathways are key in fulfilling metabolic demands of proliferating CLL cells. Among branching pathways, the pentose phosphate pathway (PPP) was the most transcriptionally upregulated in proliferating CLL cells. Increased expression of PPP genes was detected ex vivo at the bulk and single\u2010cell level in the LN\u2010resident and \u2010emigrating CLL cells, with more consistency across enzymes of the nonoxidative PPP branch. Expression of the latter correlated with shorter failure\u2010free survival in CLL patients. At the cellular level, metabolomics and 13C\u2010glucose tracing confirmed high activity of the non\u2010oxidative PPP in proliferating CLL cells. IL\u201021 regulated the expression of PPP enzymes, with STAT3 serving as the primary downstream effector. CRISPR\/Cas9\u2010mediated silencing of PPP enzymes revealed that, in vitro, proliferating CLL cells from most patients were not dependent on these enzymes. In contrast, silencing transketolase (TKT)\u2014the rate\u2010limiting enzyme of the non\u2010oxidative PPP\u2014abolished tumor engraftment in vivo, demonstrating that CLL cells rely on this pathway within the tumor microenvironment. These findings uncover a CLL\u2010specific metabolic reprogramming wherein IL\u201021\u2013STAT3\u00a0drives PPP activity and identify the nonoxidative PPP as a critical in vivo vulnerability of leukemic cells in the murine CLL model.<\/jats:p>","DOI":"10.1002\/hem3.70292","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T13:47:14Z","timestamp":1769521634000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IL21\u2014STAT3 controls the pentose phosphate pathway to support metabolic reprogramming and tumor progression in chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"10","author":[{"given":"Rosita","family":"Del Prete","sequence":"first","affiliation":[{"name":"Fondazione Toscana Life Sciences Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vjola","family":"Tusha","sequence":"additional","affiliation":[{"name":"Fondazione Toscana Life 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