{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:31:53Z","timestamp":1768505513285,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,8]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Richter\u2019s transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma.\n                  <jats:italic>MGA<\/jats:italic>\n                  (\n                  <jats:italic>Max gene associated<\/jats:italic>\n                  ), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of\n                  <jats:italic>MGA<\/jats:italic>\n                  deletion driving CLL to RT remain elusive. We established a novel RT mouse model by knockout of\n                  <jats:italic>Mga<\/jats:italic>\n                  in the\n                  <jats:italic>Sf3b1<\/jats:italic>\n                  \/\n                  <jats:italic>Mdr<\/jats:italic>\n                  CLL model via CRISPR-Cas9 to determine the role of\n                  <jats:italic>Mga<\/jats:italic>\n                  in RT. Murine RT cells exhibit mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). We identified\n                  <jats:italic>Nme1<\/jats:italic>\n                  (Nucleoside diphosphate kinase) as a\n                  <jats:italic>Mga<\/jats:italic>\n                  target through RNA sequencing and functional characterization, which drives RT by modulating OXPHOS. As\n                  <jats:italic>NME1<\/jats:italic>\n                  is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and ETC complex II significantly prolongs the survival of RT mice\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Our results suggest that\n                  <jats:italic>Mga-Nme1<\/jats:italic>\n                  axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a novel therapeutic avenue for RT.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>\n                    We established a murine RT model through knockout of\n                    <jats:italic>Mga<\/jats:italic>\n                    in an existing CLL model based on co-expression of\n                    <jats:italic>Sf3b1<\/jats:italic>\n                    -K700E and\n                    <jats:italic>del<\/jats:italic>\n                    (\n                    <jats:italic>13q<\/jats:italic>\n                    ). We determined that the\n                    <jats:italic>MGA\/NME1<\/jats:italic>\n                    regulatory axis is essential to the CLL-to-RT transition via modulation of mitochondrial OXPHOS, highlighting this pathway as a novel target for RT treatment.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.02.07.527502","type":"posted-content","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T12:40:14Z","timestamp":1675860014000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>MGA<\/i>\n                  deletion leads to Richter\u2019s transformation via modulation of mitochondrial OXPHOS"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6982-6343","authenticated-orcid":false,"given":"Prajish","family":"Iyer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiling","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevyn","family":"Hart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jibin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joo","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wing C.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven T.","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey","family":"Danilov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023021007200804000_2023.02.07.527502v1.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-09-806398"},{"key":"2023021007200804000_2023.02.07.527502v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0268-960X(97)90007-2"},{"key":"2023021007200804000_2023.02.07.527502v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/hon.880"},{"key":"2023021007200804000_2023.02.07.527502v1.4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1053\/j.seminoncol.2016.02.012","article-title":"Richter syndrome: pathogenesis and 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