# Acute myeloid leukemia (AML) Research Project

> **NIH NIH U54** · UNIVERSITY OF PENNSYLVANIA · 2024 · $218,826

## Abstract

Summary
 Acute myeloid leukemia (AML) is one of the most intensely studied of human malignancies. In recent years
there have been major advances in defining the molecular pathogenesis of AML and introduction of new
therapies. But the three-year survival rate remains below 50% indicating failures to make therapeutic advances
for the disease. In part, we believe that this reflects a failure to adequately use genetically defined PDX models
to develop new therapies targeted at molecularly defined subsets of the disease. As discussed below, although
the overall genetics of AML is complex, we and others have found that there are dominant oncogenes in AML
and that targeting of these oncogenes can induce therapeutic responses although not cures. Examples of this
approach include the use of FLT3 inhibitors for de novo and relapsed FLT3 ITD mutant AML and development
of IDH1 and IDH2 inhibitors. In each of these cases, current therapy includes a choice of targeted therapies
which are active but not curative. This likely reflects the multi-variate molecular pathogenesis. To advance the
field, we have collected thousands of independent AML collections and characterized dozens of PDX models of
AML. These models have been widely used for studies of basic biology but here we propose to advance the
use of AML PDX modeling for therapy development. There are several obstacles to progress. First, there are
not widely available and well characterized AML PDX models defined by genetic alterations. To address this
concern, we have chosen to separate AML into 7 subsets defined by dominant oncogenes as recently done by
the NIH MyeloMatch study. Leukemia’s will be sub-classified based on mutations in FLT3, DNMT3A, NPM1c,
IDH1, IDH2, TP53 or KMT2A fusion protein (FP). Here we will characterize xenotransplantation of three AML
models for each of these seven sub-groups and specifically characterize the biology of serial transplant of AML
in the NSG mouse strain. Initial documentation of engraftment has already been completed for 33 of the 35
samples. In SA2, we will focus on performance of an XP2 study to direct ongoing clinical efforts. Two of these
sub-groups are defined by the presence of fusion proteins involving KMT2A (previously mixed lineage leukemia
or MLL) or Nucleophosmin (NPM) mutations (that cause cytosolic re-localization of the protein) (NPMc). Both of
these sub-types of AML require menin, an epigenetic co-regulator for pathogenesis and AML’s with either class
of mutations responding in pre-clinical models to Menin inhibition. Menin inhibitors are currently in Phase 1 and
Phase 2 human studies and early results suggest that these drugs, like other targeted therapies in AML, are
active but not curative. Recent results have suggested that enhanced differentiation of AML samples containing
KMT2A fusion proteins (FP) can be achieved by combining a Menin inhibitor with a KAT6A inhibitor. Here we
will use our characterized KMT2A FP and NPMc mutant AML PDX models to ...

## Key facts

- **NIH application ID:** 10881943
- **Project number:** 5U54CA283759-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARTIN CARROLL
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $218,826
- **Award type:** 5
- **Project period:** 2023-07-05 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881943

## Citation

> US National Institutes of Health, RePORTER application 10881943, Acute myeloid leukemia (AML) Research Project (5U54CA283759-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10881943. Licensed CC0.

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