Identifying the pathways that drive progression of the MPNs to AML

Project: Research project

Description

The myeloproliferative neoplasms (MPNs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are closely related clonal hematopoietic disorders that are characterized by enlarged spleen, extramedullary hematopoiesis, bleeding disorders, and shortened lifespan. A major complication of the MPNs is progression to an aggressive and untreatable form of AML. This evolution to AML occurs in 5-10% of PV, 3-5% of ET patients, and 20% of PMF patients. Although mutations in p53 have been associated with progression in some patients, by and large the genetic defects that cause progression remain unknown. Identification of these genetic events 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 (aka LKB1) and RPS6KA2 (aka RSK3) as two genes whose editing cooperates with the JAK2 mutant to promote transformation in vitro. In secondary assays, we discovered that heterozygous and homozygous loss of Stk11 led to self-renewal of hematopoietic cells expressing JAK2V617F or MPLW515L, while not having this activity without enhanced JAK/STAT signaling. 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 propose to delve into the contributions of STK11 and RPS6KA2 to MPN progression by the following aims: 1) Investigate the mechanisms by which haploinsufficiency of STK11 induces progression of JAK2V617F, MPLW515L and CALR mutant MPNs to AML; and 2) Elucidate the contributions of alterations in RPS6KA2 to post-MPN AML. Together these studies will yield important new insights into the genetic basis and mechanisms by which AML arises from the MPNs. These pathways are also targetable, as there exist numerous activators of AMPK signaling and inhibitors of RPS6KA2. Therefore, the work is highly innovative and significant
StatusActive
Effective start/end date3/1/192/29/24

Funding

  • National Cancer Institute (1R01CA237039-01)

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Neoplasms
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Clustered Regularly Interspaced Short Palindromic Repeats
Extramedullary Hematopoiesis
Haploinsufficiency
AMP-Activated Protein Kinases
Splenomegaly
Hematopoietic Stem Cells
Disease Progression
Down-Regulation
Hemorrhage
Mutation
Gene Editing
Cell Self Renewal
Therapeutics