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Awakening the Sleeping Giant

December 12, 2021

 Demystifying Leukemic Stem Cells

Ah-Reum (Autumn) Jeong, MD, and Aaron M. Goodman, MD

Dr. Aaron Goodman (@AaronGoodman33) is an associate professor in the Division of Blood and Marrow Transplantation at the University of California San Diego (UCSD) Moores Cancer Center, San Diego. His specialties include bone marrow transplantation and cellular therapies, and his clinical/research interests are rare diseases, Castleman disease, and T-cell lymphomas. Dr. Goodman hails from Chicago and attended University of Illinois for undergrad, Emory for medical school, Washington University for residency, and UCSD for hematology-oncology fellowship. Dr. Goodman also offered insight into his life outside hematology. “I play in a rock band and have played guitar since age six,” he said. 

Joining Dr. Goodman this year is Junior Author Dr. Ah-Reum (Autumn) Jeong (@AutumnJeong). Dr. Jeong is a hematology/oncology fellow at Moores Cancer Center, University of California San Diego, in La Jolla, with a clinical/research interest is in lymphoma. She studied at Cornell University for undergraduate, and received her MD at University of Southern California, where she also did her internal medicine residency. She hails from Los Angeles and played lacrosse in high school. 

To some clinicians, transcriptomes, ATACseq, t-SNE, or lineage trajectories might as well be words spoken at Hogwarts. To us, leukemic stem cells (LSCs) are magical creatures that hide deep in the bone marrow, with intricate genetic signatures that are kept unspoken. Dr. Andreas Trumpp, the Harry Potter of LSCs, eloquently accomplished the job of breaking them down for us muggles in his Ham-Wasserman lecture “Normal and Leukemic Stem Cells,” presented on Saturday and available on-demand via the virtual platform. 

Since their initial discovery in the 1990s, our understanding of LSCs has dramatically changed our perception of how cancer originates and why it relapses. LSCs are genetically identical to the other cells within the same malignant clone but differ in their ability to self-renew and propagate tumor development. Strikingly, transferring only few LSCs to an immunodeficient mouse can lead to the initiation and development of leukemia. “Myeloid leukemias display a cellular hierarchy comparable to normal tissue… This seminal work by Dr. John Dick and colleagues in Toronto was the birth of the leukemic and cancer stem cell field,” Dr. Trumpp explained. These initial studies drew Dr. Trumpp, who at the time was studying normal hematopoietic stem cells (HSC), to the study of the general relationships between stem cells and cancer cells. 

Dr. Trumpp began his journey with LSCs by studying the proto-oncogene MYC, a master regulator controlling the balance between dormant and active phases of HSCs.1,2 “We subsequently identified a gene that catabolizes branched chain amino acids (BCAA) to be highly expressed in human LSCs,” said Dr. Trumpp. “And when I typed BCAA into Google, I got links to dietary supplements that are particularly popular with bodybuilders.” He flexed his biceps. “What have we found?” 

It turns out that the BCAA transaminase 1 (BCAT1) protein controls alpha-ketoglutarate, a key metabolite in the Krebs cycle. Overexpression of BCAT1 in LSCs caused a DNA hypermethylation phenotype similar to leukemic cells with IDH1/2 mutations (a mutation present in 20% of acute myeloid leukemia [AML]), which also affects the availability of alpha-ketoglutarate. This metabolite was known to function as a co-factor for the DNA demethylase TET2, closing the loop and explaining how changes in BCAA and BCAT via alpha-ketoglutarate regulate DNA methylation and LSC activity.3 

The next step was to understand why emerging LSCs were not eliminated by the immune system. Dr. Trumpp and his colleagues discovered that LSCs actively escape from immune surveillance by natural killer (NK) cells by repressing NKG2D ligands on their surface.4 They further demonstrated that PARP1 inhibition leads to the upregulation of NKG2D ligands on LSCs making them a target for allogeneic NK cells. These results were developed into a multicenter clinical trial in Heidelberg, Dresden, and Tübingen that will be accruing its first patient next year. 

Dr. Trumpp also shared exciting preliminary data using venetoclax to target LSCs. Although LSCs from different kinds of AMLs seem to be sensitive to venetoclax, they unfortunately develop resistance mechanisms including upregulation of BCL2 (venetoclax’s target) or MCL1. 

He also shed light on the mechanism of relapse due to persistence of LSCs after standard chemotherapy. “What we have found is that (the LSCs) run on different metabolic networks,” explained Dr. Trumpp. The LSCs that were isolated from patients who relapsed early relied on oxidative phosphorylation as their source of energy while the LSCs from patients who remained in long-term remission rather showed a glycolytic phenotype. The next step is to develop a predictive LSC signature to stratify patients at diagnosis and to offer alternative or adjunctive therapies, such as venetoclax, to those likely to relapse early.  

Finally, Dr. Trumpp identified two future areas of interest: therapy resistance and minimal residual disease (MRD), and prevention of leukemia. The recent progress in single-cell multi-omics technologies allows the molecular characterization of single cells, such as a single LSC, present in MRD. The development of resistance mechanisms could be studied by following the characteristics of LSCs longitudinally (at diagnosis, at MRD, and at relapse) in the same patient. “It will be key to understand the mechanism used by LSCs to survive the therapy to develop strategies to target the remaining ones in MRD or even better, improve the primary therapies to reduce resistance probabilities, which will be quite a challenge,” said Dr. Trumpp. The second topic is prevention of leukemia in people with clonal hematopoiesis caused by a single mutation in HSCs. Such pre-cancerous clones could be identified and targeted to either delay or eliminate the development of leukemia.  

“All this is challenging, but novel technologies will allow us to address these issues,” stated Dr. Trumpp. Thanks to the work of Dr. Trumpp and others, the dream of targeting LSCs may soon become a reality. 

  1. Wilson A, Laurenti E, Oser G, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118-1129. 
  2. Cabezas-Wallscheid N, Buettner F, Sommerkamp P, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169(5):807.e19-823.e19.  
  3. Raffel S, Falcone M, Kneisel N, et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature. 2017;551(7680):384-388. 
  4. Paczulla AM, Rothfelder K, Raffel S, et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature. 2019;572(7768):254-259. 

Dr. Jeong and Dr. Goodman indicated no relevant conflicts of interest.  

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