Transient Differentiation-State Plasticity Occurs During Acute Lymphoblastic Leukemia Initiation

Overview

Journal Cancer Res

Specialty Oncology

Date 2024 Jun 17

PMID 38885294

Authors

Vera M Poort

Rico Hagelaar

Markus J van Roosmalen

Laurianne Trabut

Jessica G C A M Buijs-Gladdines

Bram van Wijk

Jules Meijerink

Ruben van Boxtel

Affiliations

Soon will be listed here.

Abstract

Leukemia is characterized by oncogenic lesions that result in a block of differentiation, whereas phenotypic plasticity is retained. A better understanding of how these two phenomena arise during leukemogenesis in humans could help inform diagnosis and treatment strategies. Here, we leveraged the well-defined differentiation states during T-cell development to pinpoint the initiation of T-cell acute lymphoblastic leukemia (T-ALL), an aggressive form of childhood leukemia, and study the emergence of phenotypic plasticity. Single-cell whole genome sequencing of leukemic blasts was combined with multiparameter flow cytometry to couple cell identity and clonal lineages. Irrespective of genetic events, leukemia-initiating cells altered their phenotypes by differentiation and dedifferentiation. The construction of the phylogenies of individual leukemias using somatic mutations revealed that phenotypic diversity is reflected by the clonal structure of cancer. The analysis also indicated that the acquired phenotypes are heritable and stable. Together, these results demonstrate a transient period of plasticity during leukemia initiation, where phenotypic switches seem unidirectional. Significance: A method merging multicolor flow cytometry with single-cell whole genome sequencing to couple cell identity with clonal lineages uncovers differentiation-state plasticity in leukemia, reconciling blocked differentiation with phenotypic plasticity in cancer.

Citing Articles

Acute Myeloid Leukaemia and Acute Lymphoblastic Leukaemia Classification and Metabolic Characteristics for Informing and Advancing Treatment.

Wemyss C, Jones E, Stentz R, Carding S Cancers (Basel). 2025; 16(24.

PMID: 39766036 PMC: 11675077. DOI: 10.3390/cancers16244136.

Protocol for genome-wide analysis of somatic variants at single-cell resolution using primary template-directed DNA amplification.

Derks L, van Leeuwen A, Steemers A, Trabut L, van Roosmalen M, Poort V STAR Protoc. 2024; 6(1):103499.

PMID: 39709610 PMC: 11726792. DOI: 10.1016/j.xpro.2024.103499.

References

Rehe K, Wilson K, Bomken S, Williamson D, Irving J, den Boer M . Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations. EMBO Mol Med. 2012; 5(1):38-51. PMC: 3569652. DOI: 10.1002/emmm.201201703. View

Visvader J . Cells of origin in cancer. Nature. 2011; 469(7330):314-22. DOI: 10.1038/nature09781. View

De Bie J, Demeyer S, Alberti-Servera L, Geerdens E, Segers H, Broux M . Single-cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia. Leukemia. 2018; 32(6):1358-1369. PMC: 5990522. DOI: 10.1038/s41375-018-0127-8. View

Mitchell E, Spencer Chapman M, Williams N, Dawson K, Mende N, Calderbank E . Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022; 606(7913):343-350. PMC: 9177428. DOI: 10.1038/s41586-022-04786-y. View

Pal D, Blair H, Elder A, Dormon K, Rennie K, Coleman D . Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia. Leukemia. 2016; 30(8):1691-700. PMC: 4980562. DOI: 10.1038/leu.2016.79. View

van Galen P, Hovestadt V, Wadsworth Ii M, Hughes T, Griffin G, Battaglia S . Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell. 2019; 176(6):1265-1281.e24. PMC: 6515904. DOI: 10.1016/j.cell.2019.01.031. View

Erarslan-Uysal B, Kunz J, Rausch T, Richter-Pechanska P, van Belzen I, Frismantas V . Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors. EMBO Mol Med. 2020; 12(9):e12104. PMC: 7507092. DOI: 10.15252/emmm.202012104. View

Turati V, Guerra-Assuncao J, Potter N, Gupta R, Ecker S, Daneviciute A . Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nat Cancer. 2021; 2(8):835-852. PMC: 7611923. DOI: 10.1038/s43018-021-00219-3. View

Huang C, Kanagawa O . Ordered and coordinated rearrangement of the TCR alpha locus: role of secondary rearrangement in thymic selection. J Immunol. 2001; 166(4):2597-601. DOI: 10.4049/jimmunol.166.4.2597. View

10.

Kozlov A, Alves J, Stamatakis A, Posada D . CellPhy: accurate and fast probabilistic inference of single-cell phylogenies from scDNA-seq data. Genome Biol. 2022; 23(1):37. PMC: 8790911. DOI: 10.1186/s13059-021-02583-w. View

11.

Gawad C, Koh W, Quake S . Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc Natl Acad Sci U S A. 2014; 111(50):17947-52. PMC: 4273416. DOI: 10.1073/pnas.1420822111. View

12.

Nam A, Kim K, Chaligne R, Izzo F, Ang C, Taylor J . Somatic mutations and cell identity linked by Genotyping of Transcriptomes. Nature. 2019; 571(7765):355-360. PMC: 6782071. DOI: 10.1038/s41586-019-1367-0. View

13.

Richter-Pechanska P, Kunz J, Bornhauser B, von Knebel Doeberitz C, Rausch T, Erarslan-Uysal B . PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia. EMBO Mol Med. 2018; 10(12). PMC: 6284381. DOI: 10.15252/emmm.201809443. View

14.

Dik W, Pike-Overzet K, Weerkamp F, de Ridder D, de Haas E, Baert M . New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med. 2005; 201(11):1715-23. PMC: 2213269. DOI: 10.1084/jem.20042524. View

15.

Blackburn J, Liu S, Wilder J, Dobrinski K, Lobbardi R, Moore F . Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell. 2014; 25(3):366-78. PMC: 3992437. DOI: 10.1016/j.ccr.2014.01.032. View

16.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

17.

Behjati S, Huch M, van Boxtel R, Karthaus W, Wedge D, Tamuri A . Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature. 2014; 513(7518):422-425. PMC: 4227286. DOI: 10.1038/nature13448. View

18.

Agarwal A, Bolosky W, Wilson D, Eide C, Olson S, Fan G . Differentiation of leukemic blasts is not completely blocked in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2019; 116(49):24593-24599. PMC: 6900505. DOI: 10.1073/pnas.1904091116. View

19.

Good Z, Sarno J, Jager A, Samusik N, Aghaeepour N, Simonds E . Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. Nat Med. 2018; 24(4):474-483. PMC: 5953207. DOI: 10.1038/nm.4505. View

20.

Chaligne R, Gaiti F, Silverbush D, Schiffman J, Weisman H, Kluegel L . Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nat Genet. 2021; 53(10):1469-1479. PMC: 8675181. DOI: 10.1038/s41588-021-00927-7. View