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. 2024 Nov;38(11):2487-2491.
doi: 10.1038/s41375-024-02388-3. Epub 2024 Sep 7.

JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms

Daniel C Choi  1   2 , Nassima Messali  2 , Narasimha Rao Uda  3 , Ghaith Abu-Zeinah  1   2 , Pouneh Kermani  2 , Maria Mia Yabut  2 , Heidi E L Lischer  4 , Franco Castillo Tokumori  1   2 , Katie Erdos  1   2 , Thomas Lehmann  3 , Marta Sobas  5 , Tata Nageswara Rao  3   6 , Joseph M Scandura  7   8
Affiliations

JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms

Daniel C Choi et al. Leukemia. 2024 Nov.
No abstract available

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Conflict of interest statement

COMPETING INTERESTS

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The JAK2V617F MPN clone is excluded from lymphocytes in patients.
A Linear mixed-effects models showing the relationship between MPN duration and peripheral absolute lymphocyte count (ALC) or neutrophil count (ANC) in patients with JAK2V617F MPNs (n = 757 patients, 23,917 measurements). Significantly non-zero slope estimates are shown (t-test). B Linear regression model showing increasing JAK2V617F mutation allele frequency (MAF) in hematopoietic stem cells and multipotent progenitors (HSC/MPPs) with increasing MPN duration in the MPN cohort (n = 157). C Median MAF for HSC/MPPs, neutrophils (PMNs), erythroid progenitors (EPs), T cells, and B cells across the MPN cohort, with statistically significant differences specified (Wilcoxon matched-pairs signed rank test). D Schematic representation of the “Neutral” and “Adverse” hypotheses to explain JAK2V617F depletion in lymphocytes. E Linear regression models showing the relationship between age at clinical MPN diagnosis (left) or duration of MPN (right) and the difference between paired T cell and HSC/MPP MAF (blue) or paired PMN and HSC/MPP MAF (red) across the MPN cohort. F Mean difference between paired common lymphoid progenitor (CLP) and HSC/MPP MAF (blue) or paired myeloid progenitor (MyP) and HSC/MPP MAF (red) from patients (n = 106), with significantly non-zero differences noted (paired t-test). G Contribution of JAK2V617F CLPs to T cell differentiation in vitro is shown for each T cell precursor subpopulation with mean MAF as a blue wedge. Significant differences in MAF for each subpopulation relative to starting CLPs are specified (paired t-test). H Contribution of JAK2V617F MyPs to in vitro erythroid differentiation (as described for G). Dx = diagnosis, EB = erythroblast, CI = confidence interval.
Fig. 2
Fig. 2. JAK2V617F impairs lymphoid differentiation.
A Schematic representation of the MPN mouse models evaluated: a chimeric model (left) generated via competitive transplantation of CD45.1 recipients with CD45.1 control donor whole bone marrow (WBM) and heterozygous murine Jak2V617F knock-in CD45.2 test donor WBM, and a transgenic model (right) expressing the human JAK2V617F transgene (FF1) via hematopoietic cell-specific SclCre recombination. B Mean CD45.2 donor cell chimerism in PMNs and lymphocytes from peripheral blood (PB) of chimeric mice receiving Jak2V617F (n = 17) or Jak2WT (n = 14) donor cells. C Mean T and B cell counts from lymph nodes (LN) of JAK2V617F transgenic mice (n = 3) or wild-type controls (n = 3). D Mean CLP counts (left) and CD45.2 chimerism (right) from WBM of chimeric mice (n = 12 Jak2V617F and 11 Jak2WT recipients). E Mean CD45.2 donor cell chimerism in progressively mature thymic T cell precursors (left, n = 9 Jak2V617F and 9 Jak2WT recipients) and WBM B cell precursors (right, n = 12 JAK2V617F and 11 JAK2WT recipients) from chimeric mice. F Mean CLP counts from WBM of JAK2V617F transgenic mice (n = 7) and wild-type controls (n = 10). G Gene set enrichment analysis of RNA-seq data from JAK2V617F CLPs from transgenic mice (n = 3) using Molecular Signatures Database Hallmark gene sets and with CLPs from wild-type controls (n = 2) as the reference. The top 10 enriched gene sets (ordered by gene ratio) are split by negative (left) or positive (right) regulation in JAK2V617F CLPs relative to controls. H Experimental schema of in vitro T cell differentiation from healthy donor-derived CLPs treated with indirect Notch inhibitor (DAPT) or with vehicle control (DMSO) is shown on top. Yield of ProT cells from DMSO vs. DAPT treated healthy donor CLP cultures (n = 7, bottom left) is compared to fold change in ProT cell JAK2WT vs. JAK2V617F alleles from MPN CLP cultures (n = 16, bottom right). FDR = false discovery rate.
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