# Developing Bioinformatic and Microfluidic Single Cell Methods for Studying Intratumoral Heterogeneity in Acute Myeloid Leukemia

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $615,257

## Abstract

PROJECT SUMMARY/ABSTRACT
 It has been hypothesized that chemotherapy resistance reflects selection for a mutant clone of tumor
cells that is intrinsically resistant to chemotherapy due to its unique genetics. However, recent reports
demonstrate only a weak correlation between acute myeloid leukemia genotype and chemotherapy resistance.
As an alternative, we propose that intratumoral heterogeneity (ITH, i.e. clonal diversity) may be a predictor of
chemotherapy resistance. While one might hypothesize that increased levels of ITH relates to less tractable
disease, little data is available that definitively links ITH with outcome, let alone a relationship between the
presence of genetic diversity and gene expression or other phenotypic changes.
 While the role of clonal evolution during leukemia development and therapy has been a focus for a
number of avenues of research, the ability to deduce the clonal composition of individual samples has been
limited by the use of data from bulk tumor samples. Many of the genetic assessments of clonality performed on
cancer specimens will require the final description of clonality to be informed by single cell data rather than solely
relying on computational deconvolution of the clonal structure. Unfortunately, despite sequencing cost
reductions, the challenge of generating statistically meaningful data from single cells makes most techniques not
cost effective or flat out uninformative for this purpose. Beyond the costs, the enormous technical and
computational challenges that exist for generating and analyzing the data limit single cell analysis to research
laboratories often not involved with clinical research.
 Refining the technical ability to derive accurate data at the bulk and single cell levels, appropriately
process and interpret these data, and apply this approach to larger cohorts of patients are crucial next steps for
making relevant biological conclusions from ITH analyses. We aim to address this challenge by combining bulk-
level ITH deconvolution with single cell targeted genetic analysis using our novel microfluidic chip, and extending
this technique to include downstream transcriptomic assessments. The ability to identify genetic diversity, track
it through therapy, and connect this diversity with corresponding gene expression changes would all provide a
substantial improvement in our clinical understanding of the role of ITH in cancer therapy. With the possibility to
more directly query the genetic variability and possible transcriptomic implications of this in both model systems
as well as in primary human specimens, we can more clearly understand what role intratumoral heterogeneity
plays in human malignancy. Alternative therapies designed to level the evolutionary playing field for all clones
and reduce their frequency to a manageable level, could essentially transform an acute disease to a chronic
one. This possibility would be a valuable new clinical option for especially toxic, or poorly ...

## Key facts

- **NIH application ID:** 9834853
- **Project number:** 5R01CA226172-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Daniel T Chiu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,257
- **Award type:** 5
- **Project period:** 2018-12-10 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834853

## Citation

> US National Institutes of Health, RePORTER application 9834853, Developing Bioinformatic and Microfluidic Single Cell Methods for Studying Intratumoral Heterogeneity in Acute Myeloid Leukemia (5R01CA226172-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9834853. Licensed CC0.

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