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HiJAKing the System: Investigating the Impact Mechanisms of Low Variant Allele Frequency JAK2V617F Clone on the Pathobiology of Myeloproliferative Neoplasms

Award Number: R01CA309581
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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HiJAKing the System: Investigating the Impact Mechanisms of Low Variant Allele Frequency JAK2V617F Clone on the Pathobiology of Myeloproliferative Neoplasms - PROJECT SUMMARY/ABSTRACT JAK2V617F (JAK2V/F) is one of the Clonal Hematopoiesis if Indeterminate Potential (CHIP)-associated mutations and a major driver of myeloproliferative neoplasms (MPN). JAK2V/F is present in diverse MPN phenotypes ranging from asymptomatic low-variant allele frequency (VAF) CHIP, erythroid-specific expansion in polycythemia vera (PV), platelet overproduction in essential thrombocythemia (ET), bone marrow (BM) scarring in primary myelofibrosis (PMF) or MPN transformation into acute myeloid leukemia (AML). Highly specific JAK inhibitors fail to provide curative outcomes of MPNs, therefore searching for alternative treatment strategies is critically needed. We recently created a traceable murine JAK2V/F MPN model in which the disease is induced in the unconditioned recipients (CD45.1) of BM transplantation (BMT) with a low-VAF JAK2V/F donor clone (CD45.2). Whole BMT was performed via a single injection of the JAK2V/F donor cells into the recipients, which resulted in development of a PV-like phenotype with an average chimerism of 2.7% in the recipient peripheral blood. Post-BMT, RNA-seq analysis of the sorted CD45.2+ BM cells showed an increase in transcripts specific to early erythroblast and myeloid cells, and downregulation of those specific to lymphoid (B, T, NK) cells. Unexpectedly, transcripts specific to myeloid cells and erythroblasts also increased in the sorted CD45.1+ BM cells not bearing JAK2V/F, suggesting the BMT recipients had a skewed hematopoiesis towards a myeloproliferative phenotype. Furthermore, RNA-seq analysis of the recipient BM stroma found a loss of osteo- mesenchymal transcripts, which was corroborated by a reduction of trabecular bone observed in µCT imaging. Based on these data, we hypothesize that JAK2V/F clone, even presented at low frequencies, profoundly impacts the host hematopoietic system as well as the BM stroma, thus contributing to the MPN and multiorgan dysfunction. To test this hypothesis we will use our developed BMT strategy and cell-type specific murine models- enabled single cell RNA sequencing coupled with secretome (cytokine/chemokine, proteome and metabolome) profiling to delineate the cellular and acellular factors that mediate pathogenic effects of the JAK2V/F clone on non-mutated hematopoietic cells (Aim 1). Using our established model of BMT w/o conditioning and DARLIN lineage tracing mouse line in serial BMT approach we will determine the MPN disease-inducing potential of JAK2V617F+ clone-exposed (primed) unmutated hematopoietic cells (Aim 2). Using mesenchymal progenitor (LepR+)-specific reporter mice as unconditioned BMT recipients, we will examine the impact of JAK2V/F clone on the differentiation and function of BM mesenchymal stromal cells (Aim 3). Our data indicate that JAK2V/F CHIP clone at low frequency induces profound and irreversible alterations in its microenvironment, which then prime pathogenic phenotype of the unmutated bystander cells. The outcome of this study will generate foundational information to explain why the JAK2V/F-targeted therapies are ineffective and inform new directions in MPN therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $688,917 )
2026	2026	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cancer Biology Research	000	1	4/27/2026	NEW	$688,917
														Subtotal = $688,917

Grand Total All Awards = $688,917

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HiJAKing the System: Investigating the Impact Mechanisms of Low Variant Allele Frequency JAK2V617F Clone on the Pathobiology of Myeloproliferative Neoplasms

Award Number: R01CA309581

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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