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Directed Differentiation of Induced Pluripotent Stem Cells towards T Lymphocytes
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Transient Differentiation-State Plasticity Occurs during Acute Lymphoblastic Leukemia Initiation
Vera M Poort1,2, Rico Hagelaar1,2, Markus J van Roosmalen1,2
1Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Cancer Research
|June 17, 2024
Summary
Leukemia cells can change their identity, a process called phenotypic plasticity, even while their differentiation is blocked. This study reveals a transient window of plasticity during leukemia initiation, offering insights into cancer development and treatment.
Area of Science:
- Cancer Biology
- Hematology
- Genomics
Background:
- Leukemia is marked by blocked differentiation and retained phenotypic plasticity.
- Understanding these processes in human leukemogenesis is crucial for diagnosis and treatment.
- T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood leukemia.
Purpose of the Study:
- To pinpoint the initiation of T-cell acute lymphoblastic leukemia (T-ALL).
- To study the emergence of phenotypic plasticity during leukemogenesis.
- To link cell identity with clonal lineages in leukemia.
Main Methods:
- Combined single-cell whole genome sequencing of leukemic blasts with multiparameter flow cytometry.
- Constructed phylogenies of individual leukemias using somatic mutations.
- Coupled cell identity and clonal lineages to analyze phenotypic changes.
Main Results:
- Leukemia-initiating cells exhibited differentiation and dedifferentiation, altering phenotypes.
- Phenotypic diversity in leukemia is reflected by its clonal structure.
- Acquired phenotypes were found to be heritable and stable, with unidirectional switches during initiation.
Conclusions:
- A novel method merging flow cytometry and single-cell whole genome sequencing was developed.
- This approach uncovers differentiation-state plasticity in leukemia.
- The findings reconcile blocked differentiation with phenotypic plasticity in cancer development.
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