# Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $279,900

## Abstract

PROJECT SUMMARY
To maintain ongoing homeostasis, hematopoietic stem cells (HSCs) possess elaborate mechanisms
to balance self-renewal, proliferation and differentiation. During development and after infection HSCs
adjust self-renewal versus differentiation to expand to meet but not overshoot the needs of the
organism. Understanding how HSCs modulate this balance is critical for manipulating HSCs ex vivo
for improved use in transplantation. To improve our understanding balancing HSC self-renewal with
other needs, we have studied molecular pathways connected to the proto-oncogene, MLL1, due to its
unique ability to regulate an HSC-enriched transcriptional program and potential to become
leukemogenic upon chromosomal translocation in acute leukemia. We have shown using mouse loss-
of-function models that Mll1 is essential for the development of HSCs during embryogenesis and for
their maintenance in adult bone marrow. This role is carried out by maintaining expression of a
network of transcriptional regulators including Hoxa9, Mecom/Evi1, Prdm16 and Meis1. Therefore we
hypothesize that increasing MLL1 protein levels or activity could coordinately enhance this
transcriptional network thereby enhancing HSC self-renewal and preventing differentiation. To test
this hypothesis, we have created a new animal model that for the first time overcomes the resistance
of many cell types to overexpress wild-type MLL1. Using single-copy integration into a doxycycline-
inducible locus, we show increased hematopoietic output from embryoid bodies and embryo
progenitors upon hMLL1 induction. In this Single Aim Shine II proposal, we seek to evaluate this
animal model in detail to determine a) the developmental and differentiation stages that are
permissive for hMLL1-induced hematopoietic expansion and b) identify regulatory networks that are
altered by increased levels of MLL1 in relevant hematopoietic populations. It is our expectation that
generating this proof-of-principle data linking increased MLL1 to enhanced hematopoiesis and
determining the underlying mechanisms will guide future efforts to experimentally manipulate MLL1 in
human stem and progenitor cells to expand their numbers and improve function in transplantation
settings.

## Key facts

- **NIH application ID:** 10212374
- **Project number:** 5R01DK120369-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Patricia Ernst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $279,900
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212374

## Citation

> US National Institutes of Health, RePORTER application 10212374, Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model (5R01DK120369-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10212374. Licensed CC0.

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