Author interview: Indranil Singh is a PhD candidate in Alejo Rodríguez-Fraticelli’s laboratory at IRB Barcelona and is pursuing a doctorate in Biomedicine from the University of Barcelona. His research centers on unraveling how hematopoietic stem cell (HSC) heterogeneity influences disease initiation and progression, particularly in leukemia. To achieve this, he is developing cutting-edge methodologies such as STRACK (Simultaneous Tracking of Recombinase Activation and Clonal Kinetics) and EPI-Clone, which combine genetic barcoding and epigenetic lineage tracing to follow individual stem cell fates in physiological and pathological contexts. By elucidating the pre-existing states that prime HSCs for malignancy or tissue repair, his work offers new avenues for therapeutic intervention—from mitigating inflammatory damage after myocardial infarction to refining treatments for aggressive blood cancers.
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Lab: Alejo Rodriguez-Fraticelli, IRB Barcelona
Research Summary: We uncovered how subtle variations among stem cells, present prior to mutations, can shape the trajectory of cancer, offering a “clone-of-origin” concept that reframes our approach to diagnosis and therapy.
What was the core problem you aimed to solve with this research?
Leukaemia, in particular myeloid malignancies, remains among the most aggressive blood cancers, notorious for its low survival rates. Clinically, patients often undergo genetic analysis to find the mutation fueling their disease, but even individuals who share an identical mutation can experience markedly different outcomes. So, we asked a fundamental question: If a single mutation doesn’t uniformly dictate cancer’s course, what else might be steering how leukaemia unfolds?
We hypothesized that each stem cell’s unique “pre-existing state”—particularly its epigenetic configuration—could be key. Even before acquiring an oncogenic mutation, stem cells are known to have distinct “wiring” that influences how they grow and respond to external cues. So to test this idea, we have systematically tracked thousands of stem cells from their initial states through all the way to their eventual transformation into cancer cells. By mapping how each cell’s “previous state” impacted its behavior after acquiring the same driver mutation, we uncovered a wealth of different possible outcomes.
How did you go about solving this problem?
To tackle this question, we developed a platform called STRACK (Simultaneous Tracking of Recombinase Activation and Clonal Kinetics). In essence, STRACK integrates four key elements:
- Long-term Stem Cell Cultures: We used specialized ex vivo systems to maintain hematopoietic stem cells (HSCs) for weeks, capturing their behavior in a controlled environment.
- Precise Genetic Models: Our mouse models let us switch on relevant leukemia driver mutations, such as Dnmt3a R878H and Npm1c, at will.
- Genetic Barcoding: By tagging cells with unique “barcodes,” we could trace each clone’s lineage from normal stem cell to potential cancer cell.
- Sister-Cell Comparisons: We split populations so that half of the cells carried the mutation while their genetically “twin” counterparts remained wild-type. This allowed us to dissect how the exact same initial state would (or wouldn’t) transform under oncogenic pressure.
The result was a detailed, high-resolution map of early cancer evolution—who thrives, who falters, and who completely redefines its fate once a mutation is activated.
“We discovered that not all blood stem cells respond in the same manner when they acquire a driver mutation—their ‘previous state’ can drastically change the path the disease follows,” says Dr. Alejo Rodríguez-Fraticelli, principal investigator at IRB Barcelona and corresponding author of the study.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Think of your stem cells like a group of runners at a track—each with a different style, stamina, and speed. We gave them all the same “energy boost” (a cancer-driving mutation), then watched who broke records, who stumbled, and who changed running styles completely. The key discovery is that the final cancer “race” isn’t just about the boost but also about the runner’s starting condition. Some cells thrived wildly, becoming more aggressive, while others didn’t. Knowing this could help doctors figure out which cells to watch out for long before cancer becomes apparent. Essentially, the cell’s “memory” and environment matter every bit as much as the mutation itself.
“By revealing how these pre-existing conditions shape each cell’s response, our STRACK approach opens doors to more personalized and effective treatment strategies for leukaemia and possibly other cancers.”
What are the potential implications of your findings for the field and society?
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- Precision Oncology: If we can pinpoint which stem cell clones are likely to cause trouble, we could customize therapies and track high-risk individuals more precisely.
- Early Detection: Clinicians might one day flag suspicious clones before they evolve into full-blown cancers, improving the odds of successful intervention.
- Therapeutic Innovation: Instead of a uniform approach to “knocking out” cancer, we can envision strategies to neutralize problem clones, preserving healthy stem cells and reducing side effects.
What was the exciting moment during your research?
Over the course of this project, two events stand out as pivotal breakthroughs for me:
First, observing how driver mutations like Np1mc set off wildly different responses in our cultured stem cells was nothing short of electrifying. Seeing the heterogenity of the process with some clones exploding in number, while others limping along, reminded me that how even in a carefully controlled and reductionist approach, biology can be astonishingly unpredictable.
Second, witnessing the dramatic “switch of fate” after introducing the Npm1c mutation was similarly revelatory. We had anticipated that a mutation known to reinforce stem cell programs would intensify those same programs. Instead, in both our in-vivo mouse models and ex-vivo expansion culture, similar mutations drove cells toward entirely new identities.
Reference: Singh, Indranil, et al. “Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.” Cell Stem Cell (2025). https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00012-8
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