# Analysis of E-selectin Ligands of Human Acute Leukemia Cells and their Biology in Leukemogenesis

> **NIH NIH U01** · FLORIDA INTERNATIONAL UNIVERSITY · 2021 · $166,667

## Abstract

PROJECT SUMMARY
This application is being submitted in response to the NOSI NOT-CA-21-034. The work generated from
the parent grant (U01 CA225730) is complementary to the U54 funded DRSC at Mayo Clinic/University of
Minnesota (U54 CA224018) and we propose to perform collaborative experiments that utilize resources
from all 3 projects of this DRSC to enhance the impact of both grants. Multiple myeloma (MM) remains
incurable and the mechanisms through which MM cells develop resistance to currently available combination
regimens and recently developed immunotherapies remain incompletely understood. Our studies documented
that bone marrow (BM) mesenchymal stromal cells (BMSCs) and other nonmalignant cells of the BM/bone play
critical roles in resistance of MM, leukemia and solid tumor cells to various pharmacological agents or immune
effector cells. We observed that human MM or leukemic cells in a bicalcium phosphate (BCP) scaffold-based
BM-like in vivo system with “humanized” mesenchymal stromal compartment exhibit (compared with in vitro or
conventional subcutaneous xenografts) distinct genomic dependencies and decreased responses to diverse
therapies. Under the parent U01, we have appreciated that surface protein glycosylation plays critical roles in
regulating how malignant hematopoietic cells interact with the BM niche. Moreover, we recently observed
through CRISPR-based that perturbation of surface protein glycosylation regulators can contribute to tumor cell
resistance against pharmacological or immune-based treatments. This current project seeks to apply our the
BM-like "humanized" scaffold in vivo model; leverage our resources on regulation of surface protein
glycosylation, our experience with CRISPR-based studies in vivo and the translational relevance of the
immunocompetent Vk*myc genetically engineered mouse model (GEMM) of MM from the U54 DRSC to (1)
examine whether MM cells with high surface levels of sLeX, a key determinant of interaction of hematopoietic
cells with the BM vascular niche, exhibit more pronounced resistance to in vivo treatments within the BM niche;
and apply CRISPR-based approaches to systematically define the mechanisms of in vivo resistance of MM cells
within the BM milieu (2) against combinations of pharmacological agents; and (3) recently developed immune-
based anti-MM treatment. This project will synergistically apply the translational power of the “humanized” and
GEMM in vivo models of the collaborating programs and comprehensive CRISPR approaches to provide key
insights into how MM cells within the BM milieu develop resistance to combinations of pharmacological agents
or to immune therapies. These results will inform the U54 DRSC on preclinical testing of new approaches that
may prevent, delay or overcome these forms of treatment resistance. This collaboration will also provide a
blueprint, especially in regard to treatment resistance genes related to surface protein glycosylation, that will
accelerate the effo...

## Key facts

- **NIH application ID:** 10384552
- **Project number:** 3U01CA225730-03S1
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Constantine S. Mitsiades
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $166,667
- **Award type:** 3
- **Project period:** 2019-07-17 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10384552

## Citation

> US National Institutes of Health, RePORTER application 10384552, Analysis of E-selectin Ligands of Human Acute Leukemia Cells and their Biology in Leukemogenesis (3U01CA225730-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10384552. Licensed CC0.

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