How the same mutations give rise to very different types of leukemia microbiologystudy

Myeloid leukemias are among the most aggressive blood cancers and have low survival rates. Today, leukemia 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 has 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 the acquisition of oncogenic mutations.

“By gaining the mutations, both cell states can give rise to leukemia, 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 analyzing 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 behavior 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,” says Drs. Indranil Singh and 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 personalized therapies

The conclusions drawn by this study suggest that, for leukemia, 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 tumor 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 behavior.

Understanding these factors, as well as the mutation, would facilitate the development of even more personalized 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 laboratory at IRB Barcelona by the researchers Indranil Singh, Daniel Fernández Pérez, Pedro Sánchez Sánchez and Alejo E. Rodriguez-Fraticelli.