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Autoimmunity and persistent RAS-mutated clones long after the spontaneous regression of JMML

Leukemia volume 27, pages 1926–1928 (2013)Cite this article

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Juvenile myelomonocytic leukemia (JMML) is a chronic and aggressive myeloid leukemia in children. Patients show hepatosplenomegaly, and leukocytosis associated with monocytosis that can infiltrate the spleen, liver and lungs. About 80% of patients with JMML have a genetic abnormality in their leukemia cells, including mutations of NF1, NRAS, KRAS, CBL or PTPN11.1 Occasionally JMML cases have been reported to be associated with clinical and laboratory findings compatible with autoimmune disease.2 We and Niemela et al.3 recently proposed a novel disease entity known as RALD (RAS-associated autoimmune-lymphoproliferative syndrome (ALPS)-like disease).3, 4 RALD shows ALPS-like clinical phenotypes associated with acquired RAS mutation at certain levels of hematopoietic stem cell differentiation involving the T, B and myeloid lineages. Given the shared genetic features of common abnormality of the RAS-MAPK signaling pathway but distinct prognostic features, an important question arises as to whether RALD and JMML can be discriminated by their clinical and biological characteristics.

Direct DNA sequencing of PCR products of the RAS gene using peripheral blood mononuclear cells was performed. Surprisingly, all of the six patients showed persistent RAS mutation-positive clones, even after 3 to 19 years of follow-up after the initial diagnosis of JMML. Then we performed direct DNA sequencing of PCR products of the RAS gene in isolated T cells, B cells and myelomonocytic cells. Sequencing electropherograms showed the presence of mutated RAS alleles in all of these hematopoietic lineages (Supplementary Figure 1). To further quantitate mutated alleles in each lineage, we subcloned PCR-amplified RAS genes from T cells, B cells and myelomonocytic cells into TA cloning vector and counted the colonies that carried a mutated RAS allele. The frequency of mutated RAS alleles was between about 26 and 63% in each hematopoietic cell lineage (Figure 1b). To rule out the possibility that the mutant RAS allele was epigenetically silenced during the long survival period, we tested mRNA expression from the mutant RAS allele using peripheral blood T lymphocytes. Analysis of the reverse transcription (RT) PCR product revealed that the mutant allele was expressed as much as the wild-type allele (Supplementary Figure 2).

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References

  1. Loh ML . Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J haematol 2011; 152: 677–687.

    Article  CAS  PubMed  Google Scholar 

  2. Kitahara M, Koike K, Kurokawa Y, Sawai N, Mori T, Nakazawa K et al. Lupus nephritis in juvenile myelomonocytic leukemia. Clin Nephrol 1999; 51: 314–318.

    CAS  PubMed  Google Scholar 

  3. Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood 2011; 117: 2883–2886.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 2011; 117: 2887–2890.

    Article  CAS  PubMed  Google Scholar 

  5. Matsuda K, Shimada A, Yoshida N, Ogawa A, Watanabe A, Yajima S et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 2007; 109: 5477–5480.

    Article  CAS  PubMed  Google Scholar 

  6. Matsuda K, Yoshida N, Miura S, Nakazawa Y, Sakashita K, Hyakuna N et al. Long-term haematological improvement after non-intensive or no chemotherapy in juvenile myelomonocytic leukaemia and poor correlation with adult myelodysplasia spliceosome-related mutations. Br J haematol 2012; 157: 647–650.

    Article  PubMed  Google Scholar 

  7. Imamura M, Imai C, Takachi T, Nemoto T, Tanaka A, Uchiyama M . Juvenile myelomonocytic leukemia with less aggressive clinical course and KRAS mutation. Pediatr Blood Cancer 2008; 51: 569.

    Article  PubMed  Google Scholar 

  8. Doisaki S, Muramatsu H, Shimada A, Takahashi Y, Mori-Ezaki M, Sato M et al. Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia. Blood 2012; 120: 1485–1488.

    Article  CAS  PubMed  Google Scholar 

  9. Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y et al. Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res 2009; 65: 334–340.

    Article  CAS  PubMed  Google Scholar 

  10. Park HD, Lee SH, Sung KW, Koo HH, Jung NG, Cho B et al. Gene mutations in the Ras pathway and the prognostic implication in Korean patients with juvenile myelomonocytic leukemia. Ann Hematol 2012; 91: 511–517.

    Article  CAS  PubMed  Google Scholar 

  11. Flotho C, Kratz CP, Bergstrasser E, Hasle H, Stary J, Trebo M et al. Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. Blood 2008; 111: 966–967.

    Article  CAS  PubMed  Google Scholar 

  12. Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 1997; 89: 3534–3543.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Shino Limonov for technical support. This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan (No. 20390302 to SM) and by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan (Nos. 20-4 and 19-9 to SM and MT).

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Authors and Affiliations

  1. Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    M Takagi, J Piao, L Lin & S Mizutani

  2. Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

    H Kawaguchi

  3. Department of Pediatrics, Niigata University School of Medicine, Niigata, Japan

    C Imai

  4. Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan

    A Ogawa & A Watanabe

  5. Department of Hematology-Oncology, Saitama Children’s Medical Center, Saitama, Japan

    K Akiyama, M Mori & K Ko

  6. Department of Pediatrics, Tsukuba University School of Medicine, Tsukuba, Japan

    C Kobayashi

  7. Research Institute, National Center for Geriatrics and Gerontology, Obu City, Japan

    M Sugimoto

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  1. M Takagi
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Correspondence to M Takagi.

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Takagi, M., Piao, J., Lin, L. et al. Autoimmunity and persistent RAS-mutated clones long after the spontaneous regression of JMML. Leukemia 27, 1926–1928 (2013). https://doi.org/10.1038/leu.2013.82

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