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Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell

Leukemia volume 30, pages 1208–1210 (2016)Cite this article

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Paroxysmal nocturnal hemoglobinuria (PNH), a nonmalignant yet clonal disease that most often originates from hematopoietic stem cells (HSCs) with PIGA mutations, is characterized by intravascular hemolysis as a result of deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-APs) in erythrocytes and bone marrow failure.1, 2, 3, 4 Additional mutations in genes such as HMGA2 and JAK2 in PIGA-mutant HSCs have been implicated in the extensive expansion of PNH clones.5, 6, 7 However, the characteristics of HSCs with PIGA mutations that lead to secondary mutations and development of florid PNH are unknown. We recently treated a patient with PNH complicated by chronic myeloid leukemia (CML) using a tyrosine kinase inhibitor nilotinib alone that readily induced remission of both PNH and CML. Chronological analyses of the patient’s GPI-AP− cells and BCR-ABL mRNA copy number provided insight into the origins of CML and PNH.

A 27-year-old woman with an unremarkable personal or family medical history was referred to our hospital for a closer examination of leukocytosis with anemia identified 7 months after parturition. A complete blood count performed 15 months earlier was normal. Laboratory findings on admission were as follows: white blood cell count of 18.7 × 109/l with 1.7% stab neutrophils, 5.4% segmented neutrophils, 9.3% basophils, 1.3% promyelocytes, 5.0% myelocytes, 3.0% metamyelocytes, 18.0% lymphocytes and 0.7% blasts; hemoglobin (Hb)=6.0 g/dl, platelets=1000 × 109/l, 20.0% reticulocytes, total/direct bilirubin=1.9/0.3 mg/dl, lactate dehydrogenase (LDH)=1963 IU/l and haptoglobin <10 mg/dl. The direct Coombs test was negative. Urine test showed hemoglobinuria. Bone marrow examination revealed hypercellular marrow that had 37.6% erythroblasts and immature myeloid cells at various stages, including 0.8% myeloblasts. The karyotype was t(9;22)(q34;q11) in 20 of 20 dividing cells. BCR-ABL transcripts were amplified by reverse transcription-PCR. These findings were compatible with a diagnosis of CML in the chronic phase with a low Sokal score (0.78). Surprisingly, flow cytometry revealed that 99.2% of granulocytes and 75.7% of erythrocytes were negative for GPI-APs. The patient was thus diagnosed as having PNH complicated by CML. Administration of nilotinib at 600 mg/day was initiated in April 2013. On day 5 of treatment, the patient developed fatigue, nausea and vomiting with a high fever of 102.0 °F. Blood test showed Hb=4.3 g/dl, LDH=4164 U/l and total bilirubin=4.1 mg/dl. The exacerbation of intravascular hemolysis due to the rapid death of BCR-ABL-positive erythroblasts induced by nilotinib treatment was suspected. Nilotinib was discontinued on day 33 of treatment, and a transfusion of 280 ml of red blood cells and fluid therapy were given to ameliorate the clinical symptoms associated with massive hemolysis. Nilotinib was reinitiated at a dose of 400 mg/day after a 1-week washout period. Her peripheral blood counts and LDH levels gradually normalized thereafter without signs of hemolysis (Supplementary Figure 1). She achieved a deep molecular response as defined by the international scale at 15 months of nilotinib therapy (Table 1). Blood samples were collected from the patient for the analyses of PIGA gene and GPI-AP after informed consent according to the protocols (R-89 and 876) approved by the ethics committees of Hyogo Cancer Center and Kanazawa University Graduate School of Medical Science. A blood sample was taken from a 59-year-old woman with florid PNH for the analysis of GPI-AP as reference.

Table 1 Quantitative changes in disease markers of CML and PNH associated with nilotinib therapy
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References

  1. Lewis SM, Dacie JV . The aplastic anaemia—paroxysmal nocturnal haemoglobinuria syndrome. Br J Haematol 1967; 13: 236–251.

    Article  CAS  PubMed  Google Scholar 

  2. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal-nocturnal hemoglobinuria. Cell 1993; 73: 703–711.

    Article  CAS  PubMed  Google Scholar 

  3. Ware RE, Rosse WF, Howard TA . Mutations within the Piga gene in patients with paroxysmal nocturnal hemoglobinuria. Blood 1994; 83: 2418–2422.

    CAS  PubMed  Google Scholar 

  4. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV . Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253–1258.

    Article  CAS  PubMed  Google Scholar 

  5. Inoue N, Izui-Sarumaru T, Murakami Y, Endo Y, Nishimura JI, Kurokawa K et al. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood 2006; 108: 4232–4236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sugimori C, Padron E, Caceres G, Shain K, Sokol L, Zhang L et al. Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. Blood Cancer J 2012; 2: e63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest 2014; 124: 4529–4538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 2013; 45: 937–941.

    Article  CAS  PubMed  Google Scholar 

  9. Katagiri T, Kawamoto H, Nakakuki T, Ishiyama K, Okada-Hatakeyama M, Ohtake S et al. Individual hematopoietic stem cells in human bone marrow of patients with aplastic anemia or myelodysplastic syndrome stably give rise to limited cell lineages. Stem Cells 2013; 31: 536–546.

    Article  CAS  PubMed  Google Scholar 

  10. Katagiri T, Qi Z, Ohtake S, Nakao S . GPI-anchored protein-deficient T cells in patients with aplastic anemia and low-risk myelodysplastic syndrome: implications for the immunopathophysiology of bone marrow failure. Eur J Haematol 2011; 86: 226–236.

    Article  CAS  PubMed  Google Scholar 

  11. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ et al. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat Methods 2013; 10: 1003–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Raskind WH, Ferraris AM, Najfeld V, Jacobson RJ, Moohr JW, Fialkow PJ . Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia. Leukemia 1993; 7: 1163–1167.

    CAS  PubMed  Google Scholar 

  13. Sloma I, Jiang X, Eaves AC, Eaves CJ . Insights into the stem cells of chronic myeloid leukemia. Leukemia 2010; 24: 1823–1833.

    Article  CAS  PubMed  Google Scholar 

  14. Akashi K . Guest editorial: leukemia stem cell. Int J Hematol 2013; 98: 625–626.

    Article  PubMed  Google Scholar 

  15. Schmidt M, Rinke J, Schafer V, Schnittger S, Kohlmann A, Obstfelder E et al. Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Leukemia 2014; 28: 2292–2299.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (B), Grant Number: 24390243) and MEXT KAKENHI (Grant-in-Aid for Young Scientists (B), Grant Number: 26860363) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author contributions

RT and TK contributed equally to this work. SN developed the concept of the study and supervised the project. RT, TK and SN designed the experiments. RT, TK, KK, RKCW, SO and SN performed the experiments and analyzed the data. RT, AM, HG, IM and TM were involved in the patient’s treatment. RT, TK, KK, SO and SN wrote the paper. All authors approved the final version of this paper for submission.

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  1. R Tominaga and T Katagiri: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hyogo Cancer Center, Akashi-shi, Japan

    R Tominaga, A Maeda, H Gomyo, I Mizuno & T Murayama

  2. Division of Health Sciences, Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science, Kanazawa-shi, Japan

    T Katagiri

  3. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto-shi, Japan

    K Kataoka, K Kataoka & S Ogawa

  4. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa-shi, Japan

    R K C Wee & S Nakao

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  1. R Tominaga
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Correspondence to S Nakao.

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Tominaga, R., Katagiri, T., Kataoka, K. et al. Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell. Leukemia 30, 1208–1210 (2016). https://doi.org/10.1038/leu.2015.268

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