Abhijit Chakraborty, Ph.D.

Solving the puzzle of a shattered chromosome

FUNDED BY: the generosity of François Ferré & Magda Marquet and 2019-20 Various Donors

What was the goal of your SPARK project?

Around 40 percent of cancer patients have tumors that show a “catastrophic” chromosomal rearrangement. This suggests that an understudied phenomenon called chromothripsis, a “shattering” of the chromosome, is a key factor in cancer progression.

For my SPARK project, I studied the role of chromothripsis in triggering acute lymphoblastic leukemia (ALL), which makes up 74% of childhood leukemia diagnoses, and is the most common childhood cancers. In 2021, there were more than 5,600 new cases of ALL diagnosed in the U.S. alone. I focused on genomic rearrangements involved in chromosome 21 (iAMP21), which are linked to the highest risk ALL cases. My goal was to shed light on the health consequences of genomic rearrangements at this site—and improve our general understanding of chromothripsis. I also aimed to devise new strategies for studying genomic rearrangements as a way to predict cancer growth and provide cancer patients with accurate prognoses.

Pivoting during a pandemic

Initially, the proposed genomic analysis of my SPARK project was supposed to be carried out using ependymoma and lung cancer samples, but due to the pandemic I was unable to acquire those samples. So I had to quickly find a new collaborator in 2020, which became Dr. Anusha Preethi Ganesan, at Rady Children’s Hospital. With her help, I obtained ALL cancer samples to carry out a similar analysis and move chromothripsis research forward.

SPARK project results:

My first step was to establish a collaboration with iAMP21 and ALL expert Dr. Anusha Preethi Ganesan, an Assistant Adjunct Professor and a hematologist/oncologist at Rady Children’s Hospital, San Diego. Working with Dr. Genesan led to important cancer insights and gave us access to pediatric cancer samples.

I then performed a differential gene expression analysis between samples from iAMP21 and non-iAMP21 patients. This work showed that 1,885 genes were significantly altered between these two groups. This was a fascinating finding, and led us to uncover potential clues as to how gene expression leads to rapid progression in pediatric blood cancer with rearrangements in iAMP21. Our analysis revealed that differential and highly expressed genes in iAMP21 are involved in biological processes linked to blood formation, immune system development, myeloid cell differentiation, and other relevant functions. I also investigated gene fusion in these samples, which gave us an estimate of the level of genomic stability in the tumors.

In the end, we also devised new methods to understand 3D maps of the human genome. This research is critical for understanding chromothripsis, a devastating phenomenon in cells where shattered chromosomes can lead to especially aggressive cancer.

What’s next for this project?

We know that genomic rearrangements at iAMP21 are devastating for patients. However this project has given me reason for hope for future patients. Because iAMP21 rearrangements come with certain tell-tale gene alterations, there may be a way to expose specific vulnerabilities of cancer cells in these patients and develop targeted therapies.

Going forward, we will perform whole genome sequencing to identify structural variants at the base-pair level resolution, Hi-C to understand the alterations in 3D organization, ATAC-seq to understand genome accessibility, and ChIP-seq to explore histone modifications in iAMP21 samples.

In 2021, I received a one-year $245,000 research grant from The Conrad Prebys Foundation to expand this line of investigation further. I’m working on this grant in collaboration with the Ay and Vijayanand Labs at LJI and Rady Children’s Hospital and Children’s Oncology Group. This additional funding has been made possible by the initial SPARK funds, which allowed us to explore this area of research. My hope is that this investment by The Conrad Prebys Foundation will allow us to collect sufficient data to compete for additional substantial multi-year research funds.

By the end of 2021, I expect to have sufficient data for an important proof-of-concept research paper, which will be the first of its kind in the studies of pediatric ALL cancers and specifically for iAMP21.

What’s next for Abhijit?

My aim is to become an independent scientist, and to do so, my goal is to secure a professorship and establish my own lab at a research institute or university in the next few years. My SPARK award proved to myself and others that I can independently carry out my experiments, analysis, properly handle my own grant budget, and succeed in securing follow-on grant funding. Gaining these critical experiences not only boost my confidence that I can achieve my goals, but will also help me stand out as a potential faculty candidate in the next stage of my career.