# Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia.

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

Aberrant activation of the innate immune response is hypothesized to contribute to leukemogenesis in
myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Patients with MDS were described with
mutations that constitutively activated such pathways. Our studies suggested that mutations which impair
termination of emergency (stress) granulopoiesis (EG) are also a possible mechanism. EG is the process for
rapid, episodic granulocyte (PMN) production during infectious challenge and a key component of the innate
immune response. We previously determined that Triad1, an E3 ubiquitin (Ub) ligase, was essential for EG-
termination. Consistent with a role for a sustained EG response in leukemogenesis, we found Triad1 functioned
as a leukemia suppressor for AML with increased expression of homeodomain transcription factors. An adverse
prognosis subset of clonal myeloid malignancies, including MDS/AML with MLL1/KMT2A rearrangements, is
characterized by overexpression of a group of these proteins (e.g HoxB3, B4, A9-11, Cdx1 and 2, Meis1).
 Mice transplanted with bone marrow expressing leukemia-associated Mll1-fusion proteins develop AML after
a lag time of months; suggesting leukemogenesis requires accumulation of mutations in addition to those
involving MLL1/KMT2A-rearrangement. We found Triad1 expression decreased during leukemogenesis in a
mice with expression of an Mll1-fusion protein in the bone marrow. We also found that either Triad1 knockdown
or EG episodes accelerated AML development in such mice. We demonstrated HoxA10 enhanced, but HoxA9
repressed, Triad1 gene transcription. And, Triad1 re-expression rescued EG termination in Hoxa10-/- mice.
 We performed a screen to identify proteins with Triad1-dependent Ub. In addition to inflammatory mediators
and RTKs, we identified proteins involved in the integrated stress response (ISR; Gcn1, eIF2B4 and eIF4G1).
The ISR prevents metabolic exhaustion and cell death during sustained inflammation by modulating translation
to correct metabolic defects and enhance proliferation once defects are corrected. Gcn1 functions as a primary
regulator of this process by activating Gcn2/eIF2B4. We found Triad1-knockdown in myeloid cells altered the
profile of mRNAs undergoing translation. However, combined knockdown of Triad1 and Gcn1 in these cells
reversed abnormalities in translation of mRNAs involved in cellular response to stress, cellular response to DNA
damage, cell cycle progression, translation, protein metabolism and ISR termination with Triad1 knockdown
alone. We found Gcn1 knockdown delayed AML development in mice transplanted with bone marrow expressing
an Mll1-fusion oncoprotein, and reversed the effect of Triad1-knockdown on accelerating leukemogenesis.
 We hypothesize that inhibition of the ISR by Triad1 facilitates emergency granulopoiesis (EG)-termination
and suppresses leukemogenesis in disorders with increased Hox expression. This will be pursued by 3 Aims.
 Aim 1: Define the role of ISR in...

## Key facts

- **NIH application ID:** 10698907
- **Project number:** 2I01BX004635-05A1
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Elizabeth Ann Eklund
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10698907

## Citation

> US National Institutes of Health, RePORTER application 10698907, Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia. (2I01BX004635-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10698907. Licensed CC0.

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