Citations 2
A clinical laboratory–developed LSC17 stemness score assay for rapid risk assessment of patients with acute myeloid leukemia
Ng, Stanley , Murphy, Tracy , Mah, Michelle , Lu, Zhibin , Stickle, Natalie , Ibrahimova, Narmin, Arruda, Andrea , Mai, Ming, He, Rong , Madala, Bindu Swapna , Viswanatha, David S., Dick, John E. , Chan, Steven M. , Virtanen, Carl , Minden, Mark D. , Mercer, Tim R. , Wang, Jean , Lu, Zhibin , He, Rong , Madala, Bindu Swapna , Dick, John E , Virtanen, Carl , Minden, Mark D , Mercer, Timothy , Stockley, Tracy , Wang, Jean C Y , King, Ian F. G. , Zhang, Tong , Mitchell, Amanda
Blood Advances | December 6, 2021 | Volume: 6 | Issue: 3 | Pages: 1064-1073
10.1182/bloodadvances.2021005741
Abstract Leukemia stem cells (LSCs) are linked to relapse in acute myeloid leukemia (AML). The LSC17 gene expression score robustly captures LSC stemness properties in AML and can be used to predict survival outcomes and response to therapy, enabling risk-adapted, upfront treatment approaches. The LSC17 score was developed and validated in a research setting. To enable widespread use of the LSC17 score in clinical decision making, we established a laboratory-developed test (LDT) for the LSC17 score that can be deployed broadly in clinical molecular diagnostic laboratories. We extensively validated the LSC17 LDT in a College of American Pathologists/Clinical Laboratory Improvements Act (CAP/CLIA)-certified laboratory, determining specimen requirements, a synthetic control, and performance parameters for the assay. Importantly, we correlated values from the LSC17 LDT to clinical outcome in a reference cohort of patients with AML, establishing a median assay value that can be used for clinical risk stratification of individual patients with newly diagnosed AML. The assay was established in a second independent CAP/CLIA-certified laboratory, and its technical performance was validated using an independent cohort of patient samples, demonstrating that the LSC17 LDT can be readily implemented in other settings. This study enables the clinical use of the LSC17 score for upfront risk-adapted management of patients with AML.
Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia
Bendig, Sonja , Gu, Zhaohui , Chen, Xiaolong , Ma, Xiaotu , Murison, Alex, Zeng, Andy G.X. , Dickerson, Kirsten , Mead, Paul E., Mehr, Cyrus M., Xu, Beisi , Cheng, Zhongshan , Chang, Ti‐Cheng , Westover, Tamara , Ma, Jing , Stengel, Anna , Kimura, Shunsuke , Valentine, Marcus B., Rashkovan, Marissa , Luger, Selina M. , Litzow, Mark R. , Rowe, Jacob M. , Wang, Victoria , Yin, Jun , Loh, Mignon L. , Crews, Kristine R. , Relling, Mary V. , Evans, William E. , Paietta, Elisabeth , Ferrando, Adolfo A. , Zhang, Jinghui , Kern, Wolfgang , Haferlach, Torsten , Dick, John E. , Klco, Jeffery M. , Gu, Zhaohui , Chen, Xiaolong , Ma, Xiaotu , Abdelhamed, Sherif , Xu, Beisi , Kimura, Shunsuke , Rashkovan, Marissa , den Boer, Monique L , Yin, Jun , Hunger, Stephen P , Pui, Ching-Hon , Yang, Wenjian , Crews, Kristine R , Roberts, Kathryn G , Stock, Wendy , Zhang, Jinghui , Dick, John E , Klco, Jeffery M , Mullighan, Charles G , Loh, Mignon L , Kern, Wolfgang , Montefiori, Lindsey E. , Pölönen, Petri , García‐Prat, Laura , Iacobucci, Ilaria , Hiltenbrand, Ryan , Qu, Chunxu , Kornblau, Steven M. , Hunger, Stephen P. , Yang, Wenjian , Roberts, Kathryn G. , Yang, Jun J.J. , Stock, Wendy , Wu, Gang , Haferlach, Claudia , Mullighan, Charles G.
Cancer Discovery | June 8, 2021 | Volume: 11 | Issue: 11 | Pages: 2846-2867
Abstract Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659