# The Role of SKIDA1 in Acute Myeloid Leukemia Initiation and Maintenance

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $28,781

## Abstract

ABSTRACT
Chromosomal translocations involving the MLL1 gene often drive infant acute myeloid leukemia (AML). MLL
fusion proteins (e.g., MLL-ENL, MLL-AF9, MLL-AF10) activate self-renewal programs in hematopoietic stem
and progenitor cells, ultimately leading to transformation. The high frequency of MLL1 rearrangements in infant
leukemias suggests that neonatal progenitors are uniquely poised to transform in response to these mutations.
Indeed, we have recently shown that MLL-ENL initiates AML more efficiently in neonatal progenitors than in
adult progenitors. This raises the question of whether MLL-ENL induces key effectors of transformation more
efficiently in neonatal progenitors than in adult progenitors. We identified Ski/Dach Domain Containing 1
(Skida1) as a gene that is highly induced by MLL-ENL in neonatal, but not adult hematopoietic progenitors.
SKIDA1 is also highly expressed in human pediatric MLL1 rearranged AML. Expression is largely restricted to
leukemias with MLL1 rearrangements. To test whether Skida1 promotes leukemogenesis, we generated a
germline loss-of-function mouse allele. Skida1 deletion by itself had negligible effects on normal
hematopoiesis, consistent with the lack of expression in normal hematopoietic progenitors. Furthermore,
Skida1 deletion did not affect normal HSC function. However, when we induced MLL-ENL expression in
Skida1-/- neonates, we observed near complete loss of HSCs and a severe reduction in lineage committed
hematopoietic progenitor cells (HPCs). Thus, Skida1-dependence emerges as a consequence of MLL-ENL
expression. Next, we generated a conditional loss-of-function mouse allele. Skida1 conditional deletion in the
hematopoietic system did not perturb normal hematopoiesis at any age. We are currently crossing the
conditional Skida1 mouse to our MLL-ENL mouse model to test whether Skida1 promotes leukemogenesis in
the context of MLL-ENL-expressing progenitors. Thus, I hypothesize that Skida1 sustains pre-leukemic HSCs
and HPCs and promotes AML during neonatal stages of life. Aim 1 will use a Skida1 conditional knockout
mouse to interrogate how Skida1 sustains MLL-ENL-expressing HSCs and HPCs. I will also test whether
Skida1 is necessary to maintain fully transformed AML cells. Aim 2 builds upon Aim 1 by adding mechanistic
studies to identify Skida1-dependent changes in gene expression and cell fate. I will test whether SKIDA1
binds chromatin to regulate leukemogenesis, and I will identify SKIDA1 binding partners. The aims of this
proposal will evaluate SKIDA1 as a potential link between age-specific transcriptional programs and AML
initiation, as well as offer a novel therapeutic vulnerability for treating infant leukemia.

## Key facts

- **NIH application ID:** 10913288
- **Project number:** 5F31CA268923-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jonny Mendoza-Castrejon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $28,781
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-05-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913288

## Citation

> US National Institutes of Health, RePORTER application 10913288, The Role of SKIDA1 in Acute Myeloid Leukemia Initiation and Maintenance (5F31CA268923-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10913288. Licensed CC0.

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