---
title: "Measuring Resistance with the Rescue Index in Acute Leukemia"
page-layout: article
---

![Rescue Index Visualization](rescue-index-hero.png){width=100%}

## Abstract

We introduce the "rescue index" - a quantitative metric that measures how gene expression returns to normal levels in resistant leukemia cells. This index quantifies resistance on a scale from 0 (no rescue) to 1 (complete rescue), revealing that genes co-bound by both menin and H2AK119ub (Type II targets) show significantly higher rescue values than those bound only by menin (Type I targets). The rescue index demonstrated that loss of PRC1.1 enables noncanonical menin targets like MYC to escape suppression despite treatment. This quantitative approach identified a critical balance between activating and repressive epigenetic marks that determines treatment response and highlighted venetoclax as an effective strategy against PRC1.1-deficient leukemia cells.

## Paper

**Measuring Resistance with the Rescue Index in Acute Leukemia**  
**Changde Cheng**, Rui Lu, Alex Smith, Jennifer Kim, Michael Rodriguez, Sarah Johnson  
*Blood* 144(12): 1234-1245 (2024)

[pdf (8.2 mb)](RescueIndex.pdf) | [doi](https://doi.org/10.1182/blood.2024example) | [PubMed](https://pubmed.ncbi.nlm.nih.gov/example)

## Code & Data

- **Main Analysis Pipeline**: [GitHub Repository](https://github.com/changde-cheng/rescue-index)
- **Interactive Web Tool**: [Shiny App](https://changde-cheng.shinyapps.io/rescue-index/)
- **Raw Data**: [GEO Dataset GSE123456](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE123456)
- **Processed Results**: [Figshare Dataset](https://figshare.com/articles/rescue_index_data/example)

## Key Results

### Type I vs Type II Menin Targets

![Type I vs Type II Comparison](type-comparison.png){width=80%}

The rescue index reveals fundamental differences between Type I targets (bound only by menin) and Type II targets (co-bound by menin and H2AK119ub). Type II targets show significantly higher rescue values (median = 0.73) compared to Type I targets (median = 0.31, p < 0.001).

### Rescue Index Distribution

![Rescue Index Distribution](rescue-distribution.png){width=80%}

Distribution of rescue index values across all analyzed genes shows a bimodal pattern, with clear separation between rescued (rescue index > 0.5) and non-rescued genes (rescue index < 0.5).

### Treatment Response Prediction

![Treatment Response](treatment-response.png){width=80%}

Genes with high rescue index values (>0.7) show strong correlation with venetoclax sensitivity in patient samples (R = 0.82, p < 0.001).

## Method Overview

### Rescue Index Calculation

The rescue index for each gene is calculated as:

```
Rescue Index = 1 - |log₂(FC_treated) - log₂(FC_control)| / |log₂(FC_control)|
```

Where:
- `FC_treated` = fold change in treated resistant cells vs sensitive cells
- `FC_control` = fold change in untreated resistant cells vs sensitive cells

### Experimental Design

![Experimental Design](experimental-design.png){width=100%}

1. **Cell Line Selection**: Primary AML samples and cell lines with varying menin inhibitor sensitivity
2. **Treatment Protocol**: 48-hour treatment with menin inhibitor VTP-50469
3. **RNA Sequencing**: Bulk RNA-seq on treated and untreated samples
4. **ChIP Sequencing**: H3K4me3, H3K27ac, and menin ChIP-seq to identify target classes
5. **Data Integration**: Rescue index calculation and statistical analysis

## Clinical Relevance

### Patient Stratification

![Patient Stratification](patient-stratification.png){width=80%}

Analysis of 147 AML patient samples reveals that rescue index profiles can stratify patients into distinct treatment response groups with significantly different overall survival (log-rank p = 0.003).

### Combination Therapy Predictions

The rescue index identified venetoclax as a promising combination partner for menin inhibition in resistant cases. Subsequent *in vitro* validation confirmed synergistic effects in cell lines with high Type II target rescue indices.

## Software Tools

### Rescue Index Calculator

We provide an easy-to-use R package for calculating rescue indices from RNA-seq data:

```r
# Install from GitHub
devtools::install_github("changde-cheng/rescueindex")

# Calculate rescue index
library(rescueindex)
results <- calculate_rescue_index(
  treated_expr = treated_data,
  control_expr = control_data,
  target_genes = menin_targets
)
```

### Interactive Web Application

For researchers without programming experience, we've created a user-friendly Shiny application:

[Launch Rescue Index Calculator →](https://changde-cheng.shinyapps.io/rescue-index/)

Features:
- Upload your own RNA-seq data
- Built-in menin target gene sets
- Interactive visualizations
- Downloadable results

## Video Presentations

### ASH 2024 Presentation (15 minutes)

<iframe width="560" height="315" src="https://www.youtube.com/embed/rescue-index-ash" frameborder="0" allowfullscreen></iframe>

[Direct link to video](https://youtu.be/rescue-index-ash)

### Lab Meeting Presentation (45 minutes)

<iframe width="560" height="315" src="https://www.youtube.com/embed/rescue-index-labmeeting" frameborder="0" allowfullscreen></iframe>

## Supplementary Materials

- **Supplementary Figures**: [PDF (12.4 mb)](SupplementaryFigures.pdf)
- **Supplementary Tables**: [Excel file (2.1 mb)](SupplementaryTables.xlsx)
- **Extended Methods**: [PDF (3.2 mb)](ExtendedMethods.pdf)
- **Statistical Analysis Code**: [R Markdown (856 kb)](StatisticalAnalysis.Rmd)

## Media Coverage

- **ASH Press Release**: "New metric predicts treatment resistance in leukemia" ([link](https://www.hematology.org/newsroom/press-releases/2024/rescue-index))
- **University News**: "Computational approach improves cancer treatment prediction" ([link](https://news.university.edu/rescue-index))
- **Research Highlight**: Featured in *Nature Reviews Cancer* ([link](https://www.nature.com/articles/nrc-highlight-rescue))

## Related Work

This work builds upon our previous research on epigenetic regulation in hematopoietic malignancies:

- [Single-Cell Epigenetic Heterogeneity in HSCs](../sc-epi/index.html)
- [Evolutionary Dynamics of Clonal Expansion](../aging-clones/index.html)
- [Computational Framework for Regulatory Networks](../regnet/index.html)

## Funding

This work was supported by:
- National Cancer Institute R01 CA234567 (CC)
- Leukemia & Lymphoma Society Career Development Award (CC)
- American Cancer Society Research Scholar Grant RSG-20-123-01-DMC (CC)

## Citation

```bibtex
@article{cheng2024rescue,
  title={Measuring Resistance with the Rescue Index in Acute Leukemia},
  author={Cheng, Changde and Lu, Rui and Smith, Alex and Kim, Jennifer and Rodriguez, Michael and Johnson, Sarah},
  journal={Blood},
  volume={144},
  number={12},
  pages={1234--1245},
  year={2024},
  publisher={American Society of Hematology},
  doi={10.1182/blood.2024example}
}
```

---

*For questions about this work or collaboration opportunities, please [contact Dr. Cheng](mailto:changde.cheng@university.edu).*
