New technique reveals how the same mutations give rise to very different types of leukaemia

Myeloid leukaemias are among the most aggressive blood cancers and have low survival rates. Today, leukaemia patients undergo genetic analysis to identify mutations and select the most appropriate treatment. However, even among patients with the same mutation, disease progression and response to therapy can vary significantly.

A study led by ICREA researcher Dr. Alejo Rodríguez-Fraticelli at IRB Barcelona, and funded by Fundación CRIS contra el cáncer, has now revealed these differences can be explained by the fact that not all blood stem cells respond in the same way when they acquire a mutation, and the previous “state” of the cell influences the development of cancer.

In this regard, the researchers have identified two cell types—one “stronger” and the other more “sensitive” to inflammatory stimuli. This previous feature affects how the disease develops after acquisition of oncogenic mutations.

“By gaining the mutations, both cell states can give rise to leukaemia, but with distinct biological properties that respond in a different way to treatment,” explains Dr. Rodríguez-Fraticelli.

Published in the journal Cell Stem Cell, the findings represent a step forward in understanding the vast diversity of these types of cancers and highlight the importance of analysing the cellular "state" prior to mutation.

STRACK: high-precision tracking

To perform this study, the researchers developed the STRACK technique (Simultaneous Tracking of Recombinase Activation and Clonal Kinetics). STRACK uses genetic bar codes to track each cell and monitor its behaviour before and after acquisition of the mutation.

“This approach has allowed us for the first time to link the initial state of each cell with later cancerous features,” say Indranil Singh and Dr. Daniel Fernández Pérez, first authors of the study.

Furthermore, the use of mouse models has made it possible to study the process in a fully physiological environment, and with controlled genetic features, which reinforces the significance of the findings.

Towards more personalised therapies

The conclusions drawn by this study suggest that, for leukaemia, identifying the genetic mutation alone is not enough to determine the most appropriate treatment. The “previous state” of the cells, which can include their response to repeated inflammation or epigenetic changes, is crucial when predicting the tumour type and its response to treatment.

These findings could apply to other types of cancer as cells in distinct tissues also accumulate “memories” of inflammation or other damage, which would affect their behaviour. Understanding these factors, as well as the mutation, would facilitate the development of even more personalised treatments and preventive strategies focused on the avoidance of habits that predispose to the development of the most aggressive forms of the disease.

This study was conducted entirely in the Quantitative Stem Cell Dynamics lab at IRB Barcelona by the researchers Indranil Singh, Daniel Fernandez Perez, Pedro Sánchez Sánchez and Alejo E. Rodriguez-Fraticelli. The project received essential funding from Fundación CRIS contra el cáncer, through its programme “CRIS Excelencia 2020”, and from the European Research Council, through an ERC Starting Grant. 
 

Reference article:
Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of leukemic driver mutations
Indranil Singh, Daniel Fernandez-Perez, Pedro Sánchez Sánchez, Alejo E. Rodriguez-Fraticelli
Cell Stem Cell (2025) DOI: 10.1016/j.stem.2025.01.012