Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic <i>KRAS</i>

Osumi, Tomoo; Kato, Motohiro; Ouchi-Uchiyama, Meri; Tomizawa, Daisuke; Kataoka, Keisuke; Fujii, Yoichi; Seki, Masafumi; Takita, Junko; Ogawa, Seishi; Uchiyama, Toru; Ohki, Kentaro; Kiyokawa, Nobutaka

doi:10.1002/pbc.26496

Cited by 5 publications

(3 citation statements)

References 12 publications

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“…4,5,14 In line with previous case reports, duplication of oncogenic NRAS or KRAS from acquired uniparental disomy is associated with aggressive transformation of JMML. 39 Components of the polycomb repressive complex 2 network like EZH2 and ASXL1, or other epigenetic modifiers like DNMT3A, are mutated in about 15% of JMML patients. 4,5,40 EZH2 (7q31.2) point mutations are associated with monosomy 7, where they become hemizygous by loss of the wild-type allele.…”

Section: Cbl-mutated Jmmlmentioning

confidence: 99%

JMML genomics and decisions

Niemeyer

2018

Hematology

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Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, CBL), which define genetically and clinically distinct JMML subtypes. Three subtypes, PTPN11- , NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in non syndromic children, while two subtypes, JMML in neurofibromatosis type 1 and in JMML in children with CBL syndrome, are characterized by germ line RAS disease and acquired biallelic inactivation of the respective tumor suppressor genes in hematopoietic cells. In addition to the initiating RAS pathway lesion, secondary genetic alterations within and outside of the RAS pathway are detected in about half the patients. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive of outcome. JMML is a stem cell disorder, and most JMML patients require allogeneic stem cell transplantation for long-term survival. However, spontaneous disease regression is noted in the majority of children with CBL-mutated JMML and in some NRAS-mutated cases. In the absence of 1 of the 5 canonical RAS pathway alteration, rare mutations in other RAS genes and non-JMML myeloproliferative disorders need to be excluded. Understanding the genetic basis of myeloproliferative disorders in early childhood will greatly improve clinical decision making.

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Section: Cbl-mutated Jmmlmentioning

confidence: 99%

JMML genomics and decisions

Niemeyer

2018

Hematology

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“…In patient 1, a clone with combined PTPN11 and SETBP1 mutations was discovered, whereas a clone with a homozygous mutation in the KRAS gene was found in patient 2. Although additional alterations in the KRAS gene in JMML patients have been described as a driver of sAML transformation 20 , the percentage of identified cells with KRAS LOH in patient 2 was significantly lower than the percentage of blast cells at the time of scDNA-seq. Potential causes of sAML transformation could be the presence of mutations in genes not included in the Single-cell DNA Myeloid Kit used in this work.…”

Section: Discussionmentioning

confidence: 72%

Potential value of high-throughput single-cell DNA sequencing of Juvenile myelomonocytic leukemia: report of two cases

Volchkov,

Khozyainova,

Gurzhikhanova

et al. 2023

npj Syst Biol Appl

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Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disease of early childhood that develops due to mutations in the genes of the RAS-signaling pathway. Next-generation high throughput sequencing (NGS) enables identification of various secondary molecular genetic events that can facilitate JMML progression and transformation into secondary acute myeloid leukemia (sAML). The methods of single-cell DNA sequencing (scDNA-seq) enable overcoming limitations of bulk NGS and exploring genetic heterogeneity at the level of individual cells, which can help in a better understanding of the mechanisms leading to JMML progression and provide an opportunity to evaluate the response of leukemia to therapy. In the present work, we applied a two-step droplet microfluidics approach to detect DNA alterations among thousands of single cells and to analyze clonal dynamics in two JMML patients with sAML transformation before and after hematopoietic stem cell transplantation (HSCT). At the time of diagnosis both of our patients harbored only “canonical” mutations in the RAS signaling pathway genes detected by targeted DNA sequencing. Analysis of samples from the time of transformation JMML to sAML revealed additional genetic events that are potential drivers for disease progression in both patients. ScDNA-seq was able to measure of chimerism level and detect a residual tumor clone in the second patient after HSCT (sensitivity of less than 0.1% tumor cells). The data obtained demonstrate the value of scDNA-seq to assess the clonal evolution of JMML to sAML, response to therapy and engraftment monitoring.

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“…The finding of an aberrant B‐lymphoblast population was another unique feature for our patient. The blast phase of JMML is typically myeloid, similar to chronic myeloid leukemia (CML), though B‐ and T‐cell transformations have been reported . In CML, a minority of patients will have a small abnormal B‐lymphoblast population that does not necessarily signify impending progression to a B‐lymphoblastic phase .…”

Section: Discussionmentioning

confidence: 99%

Sustained remission with azacitidine monotherapy and an aberrant precursor B‐lymphoblast population in juvenile myelomonocytic leukemia

Hashmi

Punia

Marcogliese

et al. 2019

Pediatric Blood & Cancer

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Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a Blymphoblast population in JMML does not always progress to acute leukemia. K E Y W O R D Sazacitidine, B-lymphoblasts, JMML 1 CASEAn 11-month-old male was referred for mosaic monosomy 7, identified on peripheral blood single-nucleotide-polymorphism

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Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS

Cited by 5 publications

References 12 publications

JMML genomics and decisions

JMML genomics and decisions

Potential value of high-throughput single-cell DNA sequencing of Juvenile myelomonocytic leukemia: report of two cases

Sustained remission with azacitidine monotherapy and an aberrant precursor B‐lymphoblast population in juvenile myelomonocytic leukemia

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