# Understanding the niche of minimal residual disease leukemia cells

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $402,563

## Abstract

PROJECT SUMMARY
When acute lymphoblastic leukemia (ALL) cells evade the toxicity of cytoreductive chemotherapy, minimal
residual disease (MRD) and relapse ensue. MRD remains a major obstacle, which is unaddressed by current
therapies. Recently, integrin alpha6 (Itga6) was identified as a novel flow cytometric MRD marker. Why Itga6
marks MRD ALL cells is unknown. We developed novel models to study the emergence of MRD. This novel
MRD ALL model enables us to perform in situ characterization of bone marrow (BM) cells neighboring MRD
ALL cells and in vivo visualization of interactions of such MRD ALL cells with BM niches in real-time allowing
us to study real-time interactions of MRD ALL cells with the BM. Our preliminary data identify Itga6 as a cell
surface adhesion receptor for laminin on specific ALL cell subtypes which protects these cells against drug
treatment. However, our data also show that Itga6 has a pro-survival function independent of laminin.
Moreover, Cre-mediated deletion of Itga6 in murine pre-B ALL cells in vitro reproducibly induces apoptosis. In
xenograft model of primary ALL, combination chemotherapy treatment with P5G10, an Itga6-specific Ab,
enhanced survival of leukemia bearing mice. As our data show that the functions of Itga6 and another
adhesion molecule, Itga4, differ which also is expressed on ALL cells, differ, we will test a novel concept of
dual integrin inhibition as treatment strategy for ALL. Preliminary mass spectrometry analysis provides
mechanistic correlates of observed Itga6-associated apoptosis which provide the basis for studying the
underlying mechanism of how Itga6 promotes survival of ALL cells. Our overall hypothesis and premise for
these studies is that MRD pre-B ALL cells are located in a specific niche in the BM, and that Itga6 expression
in ALL cells is a critical component that imparts leukemia-initiating cell characteristics, including drug
insensitivity, to MRD cells. The following aims will test this hypothesis: Aim 1 will characterize the BM niche
cells in contact with MRD ALL cells in situ and in real-time in vivo and in vitro. Aim 2 determines the underlying
mechanism of Itga6-promoted MRD ALL survival. Finally, Aim 3 will preclinically evaluate the concept of Itga6
inhibition alone and in combination with Itga4 inhibition to eradicate MRD ALL. Our proposed studies may
further establish the proof-of-principle in which interruption of the Itga6/BM interaction abrogates protection of
the MRD niche to ALL, changing current concepts of treating ALL to include strategies targeting the MRD
niche.

## Key facts

- **NIH application ID:** 10002187
- **Project number:** 5R01CA172896-08
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Yong-Mi Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,563
- **Award type:** 5
- **Project period:** 2013-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002187

## Citation

> US National Institutes of Health, RePORTER application 10002187, Understanding the niche of minimal residual disease leukemia cells (5R01CA172896-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002187. Licensed CC0.

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