{"id":701,"date":"2026-02-02T20:50:13","date_gmt":"2026-02-02T20:50:13","guid":{"rendered":"http:\/\/www.rischool.org\/?p=701"},"modified":"2026-02-02T20:50:13","modified_gmt":"2026-02-02T20:50:13","slug":"to-investigate-the-possible-mechanisms-by-which225aclintuzumab-may-potentiate-or-resensitize-resistant-aml-lines-to-the-venetoclax-we-assessed-the-impact-of-the-antibody-radioconjugate-on-ce","status":"publish","type":"post","link":"http:\/\/www.rischool.org\/?p=701","title":{"rendered":"\ufeffTo investigate the possible mechanisms by which225Aclintuzumab may potentiate or resensitize resistant AML lines to the venetoclax, we assessed the impact of the antibody radioconjugate on cellular levels of antiapoptotic proteins MCL1, BCL2, and BCLXL"},"content":{"rendered":"

\ufeffTo investigate the possible mechanisms by which225Aclintuzumab may potentiate or resensitize resistant AML lines to the venetoclax, we assessed the impact of the antibody radioconjugate on cellular levels of antiapoptotic proteins MCL1, BCL2, and BCLXL. that225Aclintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclaxresistant AML cell lines through both an induction of doublestranded DNA breaks (DSBs) and depletion of MCL1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclaxresistant in vivo AML models. == Conclusions == There results suggest that the combination of225Aclintuzumab with venetoclax is usually a promising therapeutic strategy for the treatment of Fosteabine patients with venetoclaxresistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing. Keywords:225Aclintuzumab, acute myeloid leukemia, Bcl2, radioimmunotherapy, venetoclax Longterm survival of adult patients with acute myeloid leukemia (AML) remains unsatisfactory.We describe the results of a mechanistic and efficacy study combining venetoclax (ABT199), a recently approved BCL2 inhibitor, and the clinical stage CD33targeting antibody radiolabeled with225Actinium (225Aclintuzumab) in two venetoclaxresistant AML models in vitro and in vivo. The study exhibited dramatic synergy of these two drugs both in vitro and in vivo due to the decrease in BCL2 and MCL1 levels and induction of double DNA strand breaks. Since both venetoclax and225Aclintuzumab are already used in patients, we anticipate that rapid translation of this combination approach into the clinic will benefit patients with AML. == 1. INTRODUCTION == Although standard induction therapy with cytarabine and anthracycline produces complete remissions (CR) in 60% to 80% of younger adults with acute myeloid leukemia (AML), longterm survival is seen in only 25% to 50% of patients.1Following relapse, salvage chemotherapy produces remissions in only 20% to 25% of patients. Further, while allogeneic hematopoietic cell transplantation (HCT) hJAL<\/a> can result in longterm survival in approximately 30% to 40% of patients with relapsed AML, many patients are not suitable candidates for transplant due to age, comorbidities, or lack of a matched donor.1The prognosis for older patients is even worse, with a 5year median survival rate of 5% for patients older than the age of 65.2Within the last few years, following decades of limited advancement in the treatment of AML, several new targeted therapies have been approved in the US.3,4Notably, the BCL2 inhibitor venetoclax (ABT199) was approved for use in combination with a hypomethylating agent (HMA) or with lowdose cytarabine (LDAC) for the treatment of newly diagnosed patients with AML who are age 75 years or older or are ineligible for intensive chemotherapy.5,6Approval was based on the M14358 and M14387 phase Ib\/II trials. In M14358, the combination of venetoclax with azacitidine led to a complete remission (CR) rate of 37% and a CR with partial hematological recovery (CRh) rate of 24%.5For the combination of venetoclax and decitabine, the rates were 54% and 7.7%, respectively. In the M14387 trial, venetoclax in combination with lowdose cytarabine (LDAC) led to 21% CR and CRh rates.6For patients receiving all dosages of venetoclax in these studies, median overall survival was 17.5 months.5Despite the significant benefit to patients in this population, not all patients respond to initial therapy with venetoclax and most patients will eventually progress. Preclinical studies have investigated mechanisms of resistance, which are supported by clinical results in patients with progressive disease. Importantly, venetoclax as a B cell lymphoma 2 (BCL2) selective inhibitor does not inhibit other BCL family members such as myeloid cell leukemia 1 (MCL1) or B lymphoma extralarge (BCLXL). Mechanistically, overexpression of these other antiapoptotic BCL2 family members, in particular MCL1, or their upregulation in response Fosteabine to venetoclax has been shown to mediate resistance to venetoclax in leukemia, lymphoma, and multiple myeloma.7,8,9,10,11Further, MCL1 has been shown to be upregulated in AML patients at relapse following Fosteabine<\/a> induction chemotherapy.12Strategies to reduce MCL1 levels may therefore dramatically prolong the response to venetoclax and resensitize resistant tumors to venetoclax therapy. MCL1 protein has a very short halflife of less than 1 hour and is therefore sensitive to changes in RNA or protein synthesis.13To that end, genotoxic stress as a result of DNA damage, for example, by UV or ionizing radiation, or chemoinduced, can effect a reduction in MCL1 levels.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffTo investigate the possible mechanisms by which225Aclintuzumab may potentiate or resensitize resistant AML lines to the venetoclax, we assessed the…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[],"class_list":["post-701","post","type-post","status-publish","format-standard","hentry","category-nicotinic-acid-receptors"],"_links":{"self":[{"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/701","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=701"}],"version-history":[{"count":1,"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/701\/revisions"}],"predecessor-version":[{"id":702,"href":"http:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/701\/revisions\/702"}],"wp:attachment":[{"href":"http:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=701"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=701"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=701"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}