{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:52:54Z","timestamp":1760241174731,"version":"build-2065373602"},"reference-count":18,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,7]],"date-time":"2019-12-07T00:00:00Z","timestamp":1575676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The presence of the chromosomal rearrangement t(12;21)(ETV6-RUNX1) in childhood B-acute lymphoblastic leukemia (B-ALL) is an independent predictor of favorable prognosis, however relapses still occur many years later after stopping therapy, and patients often display resistance to current treatments. Since spleen tyrosine kinase (SYK), a cytosolic nonreceptor tyrosine kinase interacting with immune receptors, has been previously associated with malignant transformation and cancer cell proliferation, we aimed to assess its role in ETV6-RUNX1 cell survival and prognosis. We evaluated the effects on cell survival of three SYK inhibitors and showed that all of them, in particular entospletinib, are able to induce cell death and enhance the efficacy of conventional chemotherapeutics. By using reverse phase protein arrays we next revealed that activated SYK is upregulated at diagnosis in pediatric ETV6-RUNX1 patients who will experience relapse, and, importantly, hyperactivation is maintained at a high level also at relapse occurrence. We thus treated primary cells from patients both at diagnosis and relapse with the combination entospletinib + chemotherapeutics and observed that SYK inhibition is able to sensitize resistant primary cells to conventional drugs. Entospletinib could thus represent a new therapeutic option supporting conventional chemotherapy for relapsed ETV6-RUNX1 patients, and these evidences encourage further studies on SYK for treatment of other relapsed resistant acute lymphoblastic leukemia (ALL) subgroups.<\/jats:p>","DOI":"10.3390\/ijms20246175","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T05:54:51Z","timestamp":1575870891000},"page":"6175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["SYK Targeting Represents a Potential Therapeutic Option for Relapsed Resistant Pediatric ETV6-RUNX1 B-Acute Lymphoblastic Leukemia Patients"],"prefix":"10.3390","volume":"20","author":[{"given":"Valentina","family":"Serafin","sequence":"first","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, 35127 Padova, Italy"},{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Porc\u00f9","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuliana","family":"Cortese","sequence":"additional","affiliation":[{"name":"Department of Statistical Sciences, University of Padova, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3960-8561","authenticated-orcid":false,"given":"Elena","family":"Mariotto","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Veltri","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Bresolin","sequence":"additional","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, 35127 Padova, Italy"},{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Basso","sequence":"additional","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-1056","authenticated-orcid":false,"given":"Benedetta","family":"Accordi","sequence":"additional","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, 35127 Padova, Italy"},{"name":"Laboratory of Pediatric Oncohematology, Department of Woman\u2019s and Child\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1182\/blood-2003-10-3695","article-title":"TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity","volume":"103","author":"Morrow","year":"2004","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1038\/sj.leu.2401583","article-title":"Two cases of very late relapsing ALL carrying the TEL-AML1 fusion gene","volume":"13","author":"Chow","year":"1999","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.2174\/0929867324666170113105733","article-title":"Epratuzumab and Blinatumomab as Therapeutic Antibodies for Treatment of Pediatric Acute Lymphoblastic Leukemia: Current Status and Future Perspectives","volume":"24","author":"Franca","year":"2017","journal-title":"Curr. 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