The hidden identity of leukemia revealed by single-cell RNA sequencing

Researchers from Tokyo Medical and Dental University (TMDU) use various technologies to better characterize a rare form of leukemia on the molecular level

Leukemia is a common term used to refer to a form of blood cancer. However, there are different types of leukemia depending on the cell type involved. One unique form is myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL). Because of its rarity, there is no consensus on the specific characteristics needed to clinically identify this disease. In a recent article published in Science Advances, a team led by researchers at Tokyo Medical and Dental University (TMDU) used various approaches to better assess the molecular profile and drug sensitivity characteristics of MNKPL.

MNKPL was only first proposed as a leukemia subtype in 1997. Extramedullary involvement is one of the hallmarks of MNKPL. It is prevalent in East Asian countries. Although the immunological phenotype of MNKPL was explored previously, a full genetic characterization of this cancer type had not been performed. These details would help support more accurate diagnoses for patients, which would lead to more appropriate therapeutic decisions. Therefore, the TMDU group aimed to investigate MNKPL on a single-cell level.

Extramedullary involvement of MNKPL and origin of MNKPL revealed by single cell RNA-Sequencing

“A single-cell exploration of MNKPL would not only help us better understand its clinical and genomic features, but also clarify the specific cellular origin of this disease,” says Dr. Akira Nishimura, lead author of the study.

The team first used what is known as a multiomics approach to investigate MNKPL patient samples. They used various sequencing technologies to determine if there were any relevant mutations in specific genes, look for expression differences in certain signaling pathways at the RNA level, and examine any unique DNA methylation patterns.

“Our results demonstrate that MNKPL has molecular qualities that are distinct from other similar cancers, such as acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia,” explains Dr. Masatoshi Takagi, senior author. “Specific hallmarks of MNKPL include activation of the NOTCH1 and RUNX3, as well as lower expression of the BCL11B.”

Further work at the single-cell level in MNKPL cells showed that NK cells and myeloid cells come from a common progenitor cell type.

The researchers also conducted in vitro drug sensitivity assays where they measured MNKPL cell responses to 79 individual anti-cancer drugs.

“We observed that MNKPL cells were highly sensitive to a drug called L-asparaginase, which has already shown clinical effectiveness for this disease,” says Dr. Nishimura. “Mechanistically, we found that this was from low expression of asparagine synthetase, a quality that was distinct from other similar types of leukemia.”

Overall, the robust and comprehensive analysis performed in this study provides crucial molecular details for characterizing MNKPL. This work will undoubtedly help clinicians more effectively diagnose MNKPL and choice of therapeutic option. Additionally, this work provides data that will assist with novel therapeutic target identification and drug development in this leukemia.

SourceTokyo Medical and Dental University

Nishimura A, Yokoyama K, Naruto T, Yamagishi C, Imamura T, Nakazono H, Kimura S, Ito M, Sagisaka M, Tanaka Y, Piao J, Namikawa Y, Yanagimachi M, Isoda T, Kanai A, Matsui H, Isobe T, Sato-Otsubo A, Higuchi N, Takada A, Okuno H, Saito S, Karakawa S, Kobayashi S, Hasegawa D, Fujisaki H, Hasegawa D, Koike K, Koike T, Rai S, Umeda K, Sano H, Sekinaka Y, Ogawa A, Kinoshita A, Shiba N, Miki M, Kimura F, Nakayama H, Nakazawa Y, Taga T, Taki T, Adachi S, Manabe A, Koh K, Ishida Y, Takita J, Ishikawa F, Goto H, Morio T, Mizutani S, Tojo A, Takagi M. (2023) Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type. Sci Adv 9(50):eadj4407. [article]

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