# Mechanisms of inv(16) acute myeloid leukemia

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $426,803

## Abstract

ABSTRACT
Acute myeloid leukemia (AML) develops from dysregulated differentiation and self-renewal programs in the
hematopoietic stem cells (HSCs) or early progenitors. The leukemia fusion protein CBFβ-SMMHC represses
the transcription regulatory program of the core-binding factor RUNX1/CBFβ and generates preleukemic
myeloid progenitor cells. These cells are susceptible to induce myeloid leukemia in cooperation with other
oncogenic mutations. However, the pathways targeted by this fusion protein to induce pre-leukemic blasts, and
the pathways involved in the oncogenic switch to leukemia are not known. We have developed a small
molecule inhibitor of CBFβ-SMMHC activity that binds to the fusion protein with high specificity, and disrupts
CBFβ-SMMHC/RUNX1 binding. As a result, RUNX1/CBFβ dimers increases their occupancy at the promoters
of target genes and induces the transcription regulation of RUNX1/CBFB target genes Preliminary studies
show that pharmacologic CBFβ-SMMHC inhibition induces apoptosis in inv(16) AML cells but not to other AML
types or normal hematopoietic progenitors, suggesting an oncogene addiction switch. We hypothesize that
CBFβ-SMMHC blocks the differentiation of preleukemic cells by disrupting expression of CBF targets, and that
this event is reversible. However, the progression from preleukemia to leukemia is based on transcriptional and
chromatin changes directed by CBFβ-SMMHC-mediated regulation of RUNX1/CBFβ activity. In addition, we
will evaluate the hypothesis that this switch is due to the upregulation of MYC expression, and that in leukemic
cells (but not in preleukemic cells) MYC activity maintains the survival programs. This hypothesis will be testes
in the following three specific aims: Specific Aim 1. Determine how CBFβ-SMMHC induces MYC expression
and maintains AML survival. Specific Aim 2. Elucidate the transcription and chromatin modification directed by
CBFβ-SMMHC. Specific Aim 3. Determine the targets of CBFβ-SMMHC mediated pre-leukemia and leukemia
initiation. In summary, the proposed studies combine our expertise in core binding factor leukemia, our mouse
models for inv(16) AML and our novel pharmacologic inhibitor to investigate the mechanism of CBFβ-SMMHC
directed preleukemia and the oncogene addiction in leukemia initiation and maintenance.

## Key facts

- **NIH application ID:** 9831140
- **Project number:** 5R01CA204979-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Lucio H. Castilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,803
- **Award type:** 5
- **Project period:** 2016-12-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831140

## Citation

> US National Institutes of Health, RePORTER application 9831140, Mechanisms of inv(16) acute myeloid leukemia (5R01CA204979-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9831140. Licensed CC0.

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