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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms

Leukemia volume 38, pages 2487–2491 (2024)Cite this article

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Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how JAK2V617F hematopoiesis affects lymphoid differentiation in MPNs.

To assess the effect of JAK2V617F on hematopoiesis in our MPN cohort, we measured JAK2V617F mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45dimCD34+CD38-CD45RA-) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of JAK2V617F hematopoiesis, JAK2V617F was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in JAK2V617F MPNs.

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Fig. 1: The JAK2V617F MPN clone is excluded from lymphocytes in patients.
The alternative text for this image may have been generated using AI.
Fig. 2: JAK2V617F impairs lymphoid differentiation.
The alternative text for this image may have been generated using AI.

Data availability

The RNA-seq data have been submitted to the Gene Expression Omnibus under accession number GSE269568. Other datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Silvana Di Giandomenico, Alexandra Satty, Marina Beltrami Moreira, and Madhu Ouseph for their thoughtful suggestions and discussions. We thank Nicole Kucine for providing pediatric MPN research specimens. We acknowledge Neville Lee for consenting patients and collecting research specimens. FACS was completed through the Weill Cornell Medicine Flow Cytometry Core using instruments purchased with support from the National Institutes of Health Office of the Director grant S10 OD019986 to the Hospital for Special Surgery.

Funding

This research was supported by the Burroughs Wellcome Weill Cornell Physician Scientist Program (DCC); the Swiss National Science Foundation (320030_189090/1) and the Swiss Cancer League (KLS-5158-08-2020) (TNR); the Cancer Research & Treatment Fund (CR&T), the Myeloproliferative Neoplasms Research Foundation (MPN-RF) and MPN Peoria (JMS); and the National Center for Advancing Translational Sciences (NCATS) grant UL1 TR002384 to the Clinical and Translational Science Center (CTSC) of the Weill Medical College of Cornell University.

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Authors and Affiliations

  1. Richard T. Silver Myeloproliferative Neoplasms Center, Weill Cornell Medicine, New York, NY, USA

    Daniel C. Choi, Ghaith Abu-Zeinah, Franco Castillo Tokumori, Katie Erdos & Joseph M. Scandura

  2. Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA

    Daniel C. Choi, Nassima Messali, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Franco Castillo Tokumori, Katie Erdos & Joseph M. Scandura

  3. Department of Oncology and Hematology, Medical Research Center, Cantonal Hospital St. Gallen, St. Gallen, Switzerland

    Narasimha Rao Uda, Thomas Lehmann & Tata Nageswara Rao

  4. Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland

    Heidi E. L. Lischer

  5. Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland

    Marta Sobas

  6. Institute for Pharmacology, University of Bern, Bern, Switzerland

    Tata Nageswara Rao

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  1. Daniel C. Choi
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Contributions

DCC designed the study, performed experiments, collected and analyzed data, and wrote the manuscript; NM, PK, MMY, and FCT performed experiments; NRU, TL, and MS performed experiments and collected and analyzed data; GAZ examined and consented patients, provided blood specimens, and performed experiments; HELL analyzed data; KE consented patients, collected blood specimens, and collected data; TNR designed experiments; JMS conceived the study, examined and consented patients, provided blood specimens, and wrote the manuscript.

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Correspondence to Joseph M. Scandura.

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Choi, D.C., Messali, N., Uda, N.R. et al. JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms. Leukemia 38, 2487–2491 (2024). https://doi.org/10.1038/s41375-024-02388-3

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