# Identifying the pathways that drive progression of the MPNs to AML

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $363,268

## Abstract

PROJECT SUMMARY
The myeloproliferative neoplasms (MPNs), which include polycythemia vera, essential thrombocythemia, and
primary myelofibrosis, are closely related clonal hematopoietic disorders that are characterized by
extramedullary hematopoiesis, bleeding disorders, a shortened lifespan, and a propensity to evolve to AML.
Currently there is no way to predict which patients will develop AML, and little is known about the genetic events
that are associated with progression. The identification of drivers of leukemic transformation will improve our
understanding of the disease and provide novel targets for therapeutic intervention. To define the pathways that
drive AML progression, we performed a focused CRISPR/Cas9 screen to identify genes whose editing resulted
in hematopoietic progenitor cell self-renewal of Jak2V617F cells but not wild-type progenitors. We identified
STK11 and RPS6KA2 as two genes whose editing cooperates with the JAK2 mutant to promote transformation
in vitro. Importantly we also found that STK11 and RPS6KA2 are downregulated and mutated in post-MPN AML,
respectively, but not in chronic phase MPN. These results are highly innovative, provide significant insights into
disease progression, and reveal two new pathways to development of AML. We hypothesize that alterations in
STK11 induce AML by suppressing the activity of its substrates, including AMPK, and consequently altering
cellular metabolism and protein translation, leading to increased expression of oncogenic proteins. Similarly, we
hypothesize that genetic alterations in RPS6KA2 cause AML by impairing STK11 function and/or enhancing
mTORC1 signaling and oncogenic protein translation. We propose to delve into the contributions of STK11 and
RPS6KA2 to MPN progression by the following aims: 1) Investigate the mechanisms by which loss of STK11
induces progression of JAK2V617F mutant MPN to AML; and 2) Elucidate the contributions of alterations in
RPS6KA2 to the progression of MPN to AML. Together these studies will yield important new insights into the
genetic basis and mechanisms by which AML arises from the MPNs.

## Key facts

- **NIH application ID:** 9881289
- **Project number:** 5R01CA237039-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** John D Crispino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,268
- **Award type:** 5
- **Project period:** 2019-03-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881289

## Citation

> US National Institutes of Health, RePORTER application 9881289, Identifying the pathways that drive progression of the MPNs to AML (5R01CA237039-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9881289. Licensed CC0.

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