Discussion
Neurofibromatosis type I caused by NF1 mutations is classified as
an RAS disease (RASopathy)3, with unique phenotypic
characteristics, such as CALM, skin neurofibroma, bone dysplasia and
Lisch nodules of the iris. Patients have a high risk of benign and
malignant tumors4, with an estimated 59.6% lifetime
cancer risk and a low long-term survival rate5. A
follow-up study of 2,427 patients with neurofibromatosis type I revealed
that 9 (0.6%) patients had comorbid ALL, 2 had AML, 2 had chronic
myeloid leukemia, and one had chronic lymphocytic
leukemia6. A study including 1,021 adult patients with
newly developed AML revealed that 5% of patients had NF1 mutations, and one-third of the gene mutation loci were located at
threonine 676 (p.Thr676fs*24). This locus is associated with a lower CR
rate and shorter OS7. RAS pathway mutations occur in
more than 40% of pediatric ALL patients,8 but the
proportion of NF1 mutations is minimal, and no relevant
large-scale study findings are available.
The NF1 gene is located at chromosome 17q11.2, which spans 350
kb, including 57 constitution exons and 4 alternative spliced exons (9a,
10a2, 23a, and 48a), and encodes neurofibromin. Neurofibromin is a
RAS-GTP-activating protein that inactivates RAS-GTP by accelerating its
hydrolysis to RAS-GDP. Loss of NF1 gene expression may cause
abnormal activation of RAS and downstream signaling pathways, mainly the
RAF-MEK-ERK pathway. However, this gene also interacts with the
PI3K-AKT-mTOR pathway to influence the secondary regulation of cell
proliferation, differentiation, migration and
apoptosis9 and increases the genetic susceptibility to
benign and malignant tumors. In addition, it has been reported thatNF1 splicing site variation may trigger exon skipping, which in
turn may affect the structure and function of
proteins10. The vast majority of NF1 mutations
are intragenic, including point mutations (85% -90%) and single or
multiple exon deletions or duplications (2%). Fewer than 10% of
deletions involve the entire gene and flanking genomic
regions11. There is a strong genotype‒phenotype
correlation with 17q11.2 microdeletion syndrome12.
Detecting these mutations is dependent on multiplex ligation-dependent
probe amplification (MLPA)13. Specific mutation types
were not distinguished in this study. Thus, further research and
improvements are needed.
This study revealed that NF1 mutations do not affect the overall
effect of treatment on pediatric acute leukemia patients. Survival
outcomes are associated with adverse cytogenetic features, risk
assessment, treatment protocols, and disease progression. Patients with
germline NF1 gene mutations had a poorer prognosis than those
with somatic mutations, especially children with AML. However, all three
children with AML in this study had a high risk and concurrent adverse
genetic variants, such as KMT2A-MLLT3, MLL-AF9, andNUP98-HoxA9 . These patients had a poor remission rate after
induction therapy. Moreover, only a small number of patients were
included in this study. Therefore, the associations with prognosis
should be further investigated. ALL patients mainly had intermediate
risk, whereas AML patients mostly had high risk. Stratified therapy
based on MRD guidance has been adopted, and targeted drugs such as
blinatumomab, venetoclax and gilteritinib have been administered
simultaneously. Both the low 5-year survival rate and high recurrence
rate of AML are bottlenecks in the treatment of acute leukemia.
High-risk children should actively undergo transplantation or use
targeted drugs and new treatment protocols. In terms of fusion genes,
some ALL patients carried a ZNF384 fusion gene rearrangement,
which has not been reported previously. The transcription factor zinc
finger protein 384 gene is located at chromosome 12q13 and can fuse with
a variety of upstream partner genes, causing defects in the integrin
signaling pathway. This fusion gene is associated with premature
migration of bone marrow hematopoietic stem cells into the peripheral
blood and may be one of the mechanisms of ALL.
In this study, the clinical manifestations of neurofibromatosis included
CALM, freckles, xanthogranuloma, scoliosis, and benign intracranial
lesions. No other benign or malignant tumors were discovered.
Neurofibromatosis was more common in patients with germline NF1 gene mutations, which is consistent with the findings of previous
studies14,15. Somatic NF1 gene mutations were
mostly acquired cytogenetic mutations secondary to leukemic tumor cells.
However, the possibility of chimeric mutations should be considered when
patients present with clinical symptoms of neurofibromatosis. The
clinical symptoms of neurofibromatosis are atypical, variable and appear
gradually over time because of incomplete penetrance of the NF1 gene in children and adolescents. When germline NF1 gene
mutations are identified or the patient exhibits relevant clinical
symptoms, the French Neurofibromatosis Type I Guidelines 2020 should be
followed for clinical follow-up16.
In the CNS, bright signals in the cerebellum, brainstem, thalamus and
basal ganglia occur in 70% of children with neurofibromatosis; these
signals indicate benign brain lesions that appear at approximately 3
years of age and gradually disappear between 20 and 30 years of
age17. In this study, abnormal head nuclear magnetic
resonance signals were observed in all three neurofibromatosis patients
at the first visit, and these signals were slightly reduced during
chemotherapy. Patient ALL-3 had more abnormal signals after drug
withdrawal than before withdrawal. These lesions do not affect brain
function or intellectual development. Optic pathway gliomas (OPGs) are
the most common CNS tumors in children under 7 years of age withNF1 mutations, with an incidence of 15–20%. However, these
patients are mostly asymptomatic,18 and no OPGs were
found in this study.
Patients with neurofibromatosis mainly receive symptomatic treatment.
The MEK inhibitor selumetinib is approved by the US Food and Drug
Administration for the treatment of children with NF1 -associated
plexiform neurofibromas. Interestingly, some studies have shown that the
TKI inhibitors imatinib and nilotinib may decrease the volume of
plexiform neurofibromas19,20. These two drugs are also
used in Philadelphia chromosome-positive ALL patients, suggesting that
the potential value of targeted drugs deserves further investigation in
these patients.
In conclusion, this study is a single-center retrospective study with
the largest number of children with NF1 mutation-positive acute
leukemia available in China. However, most children have not stopped
drug treatment. Further follow-up studies are needed to determine the
long-term prognosis of these patients.
Conflict of Interest statement: The manuscript has no conflicts
of interest.
Acknowledgements: Thank all the leukemia patients and their
parents who provided cases, and thank all the medical staff who worked
hard for it.
Ethics statement: We have affirm that informed consent of the
case patients has been properly documented.
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Table 1 Clinical characteristics of patients with NF1 mutation-positive acute leukemia