Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation

Hiramoto, Rika; Imamura, Toshihiko; Muramatsu, Hideki; Wang, Xinan; Kanayama, Takuyo; Zuiki, Masashi; Yoshida, Hideki; Moroto, Masaharu; Fujiki, Atsushi; Chiyonobu, Tomohiro; Osone, Shinya; Ishida, Hiroyuki; Kojima, Seiji; Hosoi, Hajime

doi:10.1007/s12185-015-1877-y

Cited by 3 publications

(3 citation statements)

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“…It is known that hematopoietic cells may migrate and reside in nonhematopoietic tissues, including buccal mucosa and, more surprisingly, finger nails. 45,46 However, cultured fibroblasts that could be tested in some of the patients are devoid of contamination with hematopoietic cells. 26,41,42 Together with the systemic clinical features observed in all our patients, it is likely that NRAS changes affecting Gly12 were indeed of germline origin.…”

Section: Discussionmentioning

confidence: 99%

Genotype and phenotype spectrum of NRAS germline variants

et al. 2017

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RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.

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Section: Discussionmentioning

confidence: 99%

Genotype and phenotype spectrum of NRAS germline variants

et al. 2017

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“…30,31 The prolonged duration in JMML might be attributed to the failure to achieve genetic remission pre-HSCT and the heterogeneous distribution of pathogenic cells originating from earlier-stage stem cells. 32,33 Consequently, the transplant requires a longer duration to eliminate JMML-associated cells thoroughly. Current research supports the benefits of demethylation therapy for JMML patients.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike JMML, acute leukaemia can usually achieve MRD negativity early after HSCT using methods like MFC or ddPCR 30,31 . The prolonged duration in JMML might be attributed to the failure to achieve genetic remission pre‐HSCT and the heterogeneous distribution of pathogenic cells originating from earlier‐stage stem cells 32,33 . Consequently, the transplant requires a longer duration to eliminate JMML‐associated cells thoroughly.…”

Section: Discussionmentioning

confidence: 99%

Droplet digital PCR: An effective method for monitoring and prognostic evaluation of minimal residual disease in JMML

Mao,

Lin,

Qin

et al. 2024

Br J Haematol

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SummaryJuvenile myelomonocytic leukaemia (JMML) is a rare myeloproliferative neoplasm requiring haematopoietic stem cell transplantation (HSCT) for potential cure. Relapse poses a significant obstacle to JMML HSCT treatment, as the lack of effective minimal residual disease (MRD)‐monitoring methods leads to delayed interventions. This retrospective study utilized the droplet digital PCR (ddPCR) technique, a highly sensitive nucleic acid detection and quantification technique, to monitor MRD in 32 JMML patients. The results demonstrated that ddPCR detected relapse manifestations earlier than traditional methods and uncovered molecular insights into JMML MRD dynamics. The findings emphasized a critical 1‐ to 3‐month window post‐HSCT for detecting molecular relapse, with 66.7% (8/12) of relapses occurring within this period. Slow MRD clearance post‐HSCT was observed, as 65% (13/20) of non‐relapse patients took over 6 months to achieve ddPCR‐MRD negativity. Furthermore, bone marrow ddPCR‐MRD levels at 1‐month post‐HSCT proved to be prognostically significant. Relapsed patients exhibited significantly elevated ddPCR‐MRD levels at this time point (p = 0.026), with a cut‐off of 0.465% effectively stratifying overall survival (p = 0.007), event‐free survival (p = 0.035) and cumulative incidence of relapse (p = 0.035). In conclusion, this study underscored ddPCR's superiority in JMML MRD monitoring post‐HSCT. It provided valuable insights into JMML MRD dynamics, offering guidance for the effective management of JMML.

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