Clonal hematopoiesis is driven by aberrant activation of TCL1A
Authors: Weinstock Joshua S. , Gopakumar Jayakrishnan , Burugula Bala Bharathi , Uddin Md Mesbah , Jahn Nikolaus , Belk Julia A. , Daniel Bence , Ly Nghi , Mack Taralyn M. , Laurie Cecelia A. , Broome Jai G. , Taylor Kent D. , Guo Xiuqing , Sinner Moritz F. , von Falkenhausen Aenne S. , Kääb Stefan , Shuldiner Alan R. , O’Connell Jeffrey R. , Lewis Joshua P. , Boerwinkle Eric , Barnes Kathleen C. , Chami Nathalie , Kenny Eimear E. , Loos Ruth J. , Fornage Myriam , Hou Lifang , Lloyd-Jones Donald M. , Redline Susan , Cade Brian E. , Psaty Bruce M. , Bis Joshua C. , Brody Jennifer A. , Silverman Edwin K. , Yun Jeong H. , Qiao Dandi , Palmer Nicholette D. , Freedman Barry I. , Bowden Donald W. , Cho Michael H. , DeMeo Dawn L. , Vasan Ramachandran S. , Yanek Lisa R. , Becker Lewis C. , Kardia Sharon , Peyser Patricia A. , He Jiang , Rienstra Michiel , Harst Pim Van der , Kaplan Robert , Heckbert Susan R. , Smith Nicholas L. , Wiggins Kerri L. , Arnett Donna K. , Irvin Marguerite R. , Tiwari Hemant , Cutler Michael J. , Knight Stacey , Muhlestein J Brent. , Correa Adolfo , Raffield Laura M. , Gao Yan , Andrade Mariza de , Rotter Jerome I. , Rich Stephen S. , Tracy Russell P. , Konkle Barbara A. , Johnsen Jill M. , Wheeler Marsha M. , Smith J. Gustav , Melander Olle , Nilsson Peter M. , Custer Brian S. , Duggirala Ravindranath , Curran Joanne E. , Blangero John , McGarvey Stephen , Williams L. Keoki , Xiao Shujie , Yang Mao , Gu C. Charles. , Chen Yii-Der Ida. , Lee Wen-Jane , Marcus Gregory M. , Kane John P. , Pullinger Clive R. , Shoemaker M. Benjamin , Darbar Dawood , Roden Dan , Albert Christine , Kooperberg Charles , Zhou Ying , Manson JoAnn E. , Desai Pinkal , Johnson Andrew , Mathias Rasika , Blackwell Thomas W. , Abecasis Goncalo R. , Smith Albert V. , Kang Hyun M. , Satpathy Ansuman T. , Natarajan Pradeep , Kitzman Jacob , Whitsel Eric , Reiner Alexander P. , Bick Alexander G. , Jaiswal Sidd 
Published: December 2021

A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.