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Case Reports
. 2025 Jul;104(7):3881-3887.
doi: 10.1007/s00277-025-06417-8. Epub 2025 May 24.

Subclonal emergence of polycythemia vera, chronic myelomonocytic leukemia, and chronic myeloid leukemia

Violaine Tran Quang  1   2 , Jules Cretin  1   2 , Romain Loyaux  1 , Bilel Ben Jedidia  1 , Sihem Tarfi  1   2 , Guillaume Gricourt  1 , Quentin Barathon  2 , Corine Joy  2 , Pascaline Etancelin  3 , Orianne Wagner-Ballon  1   2 , Cécile Pautas  4 , Lydia Roy  4 , Ivan Sloma  5   6
Affiliations
Case Reports

Subclonal emergence of polycythemia vera, chronic myelomonocytic leukemia, and chronic myeloid leukemia

Violaine Tran Quang et al. Ann Hematol. 2025 Jul.

Abstract

The present longitudinal study reports a unique patient followed over almost three decades who sequentially developed polycythemia vera, chronic myelomonocytic leukemia, and chronic myeloid leukemia. The patient received successive hydroxyurea, ruxolitinib, and a combination of ruxolitinib and nilotinib. The clonal architecture dynamic was reconstructed using targeted high throughput asymmetric capture sequencing, allowing detection and quantification of mutations in 43 myeloid genes and BCR::ABL1 fusion in multiple bone marrow or peripheral blood samples and in single cell-derived colonies obtained from bone marrow colony-forming cell assays. This analysis has uncovered an unexpected subclonal link between three myeloid malignancies, all stemming from a DNMT3A/TET2 double mutant clone. Over a period of more than 30 years, this clone underwent major telomere shortening. However, a striking sustained major molecular response of the terminal dominant clone carrying all driver mutations was achieved by combination therapy with nilotinib and ruxolitinib. The remaining clone driving both polycythemia and chronic myelomonocytic leukemia remained unaffected and evolved to myelofibrosis and proliferative CMML.

Keywords: Chronic myeloid leukemia; Chronic myelomonocytic leukemia; Co-occurrence; Dual targeting; Dual targeting myeloproliferative neoplasm; Polycythemia vera; Ruxolitinib; Telomere; Tyrosine kinase inhibitor; aCAP-Seq.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This case report complied with French regulations and was approved by the Henri Mondor. Institutional Review Board (No. 00011558). The study methodologies conformed to the standards set by the Declaration of Helsinki. All patient data were anonymized and de-identified before analysis, and informed consent was obtained from all patients. Consent for publication: All authors have agreed with the content of the manuscript for publication. Competing interests: IS is a speaker for Novartis and Incyte. IS is a co-inventor of a know-how licensed by AP-HP to Agilent Technologies. OWB has a patent issued relevant to this work. Other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Serial development of three hematological malignancies (A) Peripheral blood parameters: hematocrit (%), hemoglobin level (g/dL), white blood cell count (WBC, 109/L), and absolute monocyte count (AMC, 109/L). Normal ranges are indicated with dotted lines (B). UPN1 monocyte subsets were analyzed with Navios cytometer (Beckman Coulter®) and Kaluza Analysis software (v2.2.1, Beckman Coulter®). (C) BCR::ABL1 transcripts and JAK2V617F quantifications were done using GeneXpert (Cepheid®) and QX200 ddPCR (assay dHsaMDV27944642, Biorad®) or MutaQuant (Qiagen®) qPCR, respectively. cMo: CD14 + + CD16- classical monocytes; PV: Polycythemia vera
Fig. 2
Fig. 2
A complex clonal architecture (A) Ten clones were identified by NGS sequencing on single-cell derived colonies, peripheral blood, and bone marrow. (B) Clonal hierarchy leading to the emergence of three hematological malignancies. Biallelic inactivation of TET2 in clone Y suggested chronic myelomonocytic leukemia was secondary to polycythemia vera and developed before chronic myeloid leukemia. (C) NGS analyses were performed on single cell-derived colonies (n = 32) at CML diagnosis and six months after nilotinib initiation. Libraries were prepared using an in-house protocol with a pre-pooling capture-based enrichment method (SureSelect XT-HS1 library prep kit, Agilent) and aCAP-seq [2] to quantify BCR::ABL1 fusion, 43 genes, and mutational hotspots. Paired-end sequences were obtained on MiSeq (cartridge V3, 2 × 300 bp, Illumina). NGS sequencing was also performed on total PB (n = 4) and BM samples (n = 3) collected from 1997 to 2020 (dot lines) using the XT-HS1 capture protocol as previously described6. JAK2 polymorphisms (rs2230724, rs10974955, rs3837256, rs10815163 from dbSNP build 156) were used to quantify the JAK2V617F homozygous clone burden. A matrix of the clonal hierarchy evolution was then constructed and plotted using the fishplot R package (v0.5), completed with manual annotations. Due to their low VAF, NRAS clones were randomly plotted on the fishplot. PV: Polycythemia vera. CMML: Chronic myelomonocytic leukemia. CML: Chronic myeloid leukemia
Fig. 3
Fig. 3
A reduced telomere length Telomere length per chromatid measurements of healthy individuals (open circles and black line for linear regression fitting line), UPN1 (red), UPN2 (blue), UPN3 (green), UPN4 (brown), UPN5 (orange), and UPN6 (pink). Linear regression with 95% confidence interval (dot lines) and slopes were calculated with Prism v10.2.3 (GraphPad®). Relative telomere lengths were measured by qPCR, and then absolute values were calculated using a reference human genomic DNA sample with known telomere length (Absolute Human Telomere Length Quantification qPCR Assay Kit, ScienCell®). CML: chronic myeloid leukemia; CMML: Chronic myelomonocytic leukemia; cMo: CD14 + + CD16- classical monocytes; PV: Polycythemia vera
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References

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