The relationship between several gene mutations and prognosis in acute myeloid leukemia (part 1)

Author: LIU Jia Jun, Third Affiliated Hospital of Sun Yat-sen Hematology article is the author's permission NMT Medical publish, please do not reprint without authorization
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Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells
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In the process of diagnosis, treatment and prognosis of AML, genetic abnormality is an important indicator
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With the continuous advancement of genetic testing technology, more and more genes related to the occurrence of AML have been discovered, and these genes have important significance in guiding the prognosis
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Therefore, this article refers to the AML risk stratification system established by the European Leukemia Network (ELN) in 2017 based on karyotype and genetic abnormalities, and focuses on the genes with clear evidence that are related to the prognosis of AML and their relationship with the prognosis
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1RUNX1-RUNX1T The translocation of chromosome 18 and chromosome 21 [t(8;21)(q22;q22)] is the basis of the RUNX1/RUNX1T1 fusion gene
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The etiology and clinical features of AML caused by the RUNX1/RUNX1T1 fusion gene and the CBFB-MYH11 fusion gene are similar, and are collectively referred to as CBF-AML[1]
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However, the two have different effects on the prognosis, so they are discussed separately
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Core binding factor (CBF) plays an important role in the production of hematopoietic stem cells and the process of hematopoiesis.
RUNX1 encodes the ɑ subunit in CBF, which is responsible for direct binding to DNA
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Therefore, the production of the RUNX1/RUNX1T1 fusion gene will disrupt the function of CBF, leading to blocking of myeloid differentiation and ultimately leading to leukemia
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According to retrospective studies conducted abroad, the prognosis of RUNX1/RUNX1T1 positive AML is good, with a complete remission (CR) rate of 87%-98%, and a 5-year disease-free survival (DFS) rate of 45%-52%, 5 The annual overall survival (OS) rate is 45%-69%
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AML with other mutant genes has a poorer prognosis
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For example, AML with KIT gene mutations usually has a poor prognosis, and the incidence of KIT gene mutations in CBF-AML is higher (17%-38%)
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As far as the current research is concerned, the combination of KIT gene mutations can reduce the DFS of RUNX1/RUNX1T1 positive AML patients, but the impact on OS is still controversial
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As for the influence of other mutant genes such as FLT3 on the prognosis, it is still uncertain [2]
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2CBFB-MYH11CBFB-MYH11 fusion gene is the result of chromosomal rearrangement, inv(16)(p13.
1q22) is more common, and the less common type is t(16;16)(p13.
1;q22)
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The fusion gene is associated with the occurrence of M4 AML, and is characterized by the presence of bone marrow monocyte blasts and atypical eosinophils
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The mouse model showed that the CBFB-MYH11 fusion gene can disrupt the function of core binding factor (CBF), leading to blocking of myeloid differentiation and ultimately leading to leukemia
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Although the expression of CBFB-MYH11 alone is not enough to cause leukemia, the combination of CBFB-MYH11 and other mutations can specifically lead to the development of myeloid leukemia [1]
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The prognosis of leukemia caused by the pure CBFB-MYH11 fusion gene is better.
Studies have shown that the CR rate of CBFB-MYH11 positive AML can reach 85%-93%, the 3-year DFS rate is 48%-58%, and the 5-year OS rate is 50 %-61%
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However, patients with AML who have other mutated genes have a poorer prognosis
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For example, AML with KIT gene mutation usually has a poor prognosis, while KIT gene mutation has a higher incidence in CBF-AML (17%-38%)
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As far as the current research is concerned, compared with RUNX1/RUNX1T1 positive AML, the combined KIT gene mutation will reduce the DFS of CBFB-MYH11 positive AML, but has little effect on OS
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As for the influence of other mutant genes such as FLT3 on the prognosis, it is not yet fully determined [2]
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3NPM1 nucleophosmin 1 (nucleophosmin 1, NPM1) belongs to the nucleophosmin family and is a widely expressed phosphoprotein that can shuttle between nucleolus, nucleoplasm and cytoplasm
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The gene is located at 5q35, contains 12 exons, and encodes 3 nucleophosphoprotein subtypes
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NPM1 has four main functions: (1) Participate in ribosome biosynthesis; (2) Maintain gene stability; (3) Rely on p53 stress response; (4) Regulate growth inhibitory pathway through ARF-p53 interaction [3]
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The mechanism of NPM1 gene mutation and the pathogenesis of AML is unclear
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Abnormal cytoplasmic dislocation is a common feature of all NPM1 mutants, and may play a very important role in the occurrence of leukemia
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However, the exact mechanism that causes leukemia has not yet been elucidated
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The effect of NPM1 gene mutation on the prognosis is closely related to the co-mutation gene FLT3-ITD
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According to the 2017 ELN guidelines, NPM1 gene mutations are not accompanied or accompanied by low FLT3-ITD expression (low allele ratio [<0.
5]; high allele ratio [>0.
5]; semi-quantitative FLT3-ITD allele ratio Evaluate [using DNA fragment analysis] as the area under the curve ratio [AUC] "FLT3-ITD" divided by AUC "FLT3-wild type")
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The guidelines point out that AML with NPM1 mutation and FLT3-ITD low allele ratio may have a better prognosis, and patients should not routinely undergo allogeneic hematopoietic cell transplantation [4]
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NPM1 gene mutations without FLT3-ITD gene mutations have a better prognosis.
According to ELN risk classification and retrospective studies conducted abroad, NPM1 gene mutations without FLT3-ITD and NPM1 gene mutations with low FLT3-ITD expression have a better prognosis.
The prognosis of patients with NPM1 gene mutation and FLT3-ITD high expression is poor
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NPM1 gene mutation without FLT3-ITD and NPM1 gene mutation with FLT3-ITD low expression OS, event-free survival (EFS), cumulative recurrence rate (CIR), cumulative mortality (CID) are better than NPM1 gene mutation combined FLT3-ITD high expression [5]
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4CEBPACCAAT enhancer binding protein α gene (CCAAT/en-hancer binding protein α, CEBPA) belongs to the leucine zipper transcription factor family and is located on chromosome 19q13
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CEBPA mutations can up-regulate the genes for hematopoietic stem cell homing and granulocyte differentiation, down-regulate the genes of signal molecules and transcription factors involved in regulating the proliferation of hematopoietic cells, hinder the evolution of DNA from G1 to S phase, and induce the maturation of advanced hematopoietic cells, leading to the development of leukemia
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The incidence of CEBPA gene mutations accounts for 5%-14% of adult AML patients
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Mutations can be divided into double mutations and single mutations.
N-terminal frameshift mutations and C-terminal in-frame mutations are more common, while single heterozygous mutations are not common
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Many studies at home and abroad have shown that the prognosis of double mutation is good.
Both the CR rate and the total CR rate after maintenance chemotherapy in the CEBPA double mutation group are significantly higher than the CEBPA monomer mutation group and the CEBPA negative group, and the median OS (60 cases) Months) and median EFS (53 months) were significantly longer than the other two groups [6]
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Both the WHO and ELN guidelines on AML consider the CEBPA gene double mutation as a sign of good prognosis
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5MLLT3-KMT2AMLLT3-KMT2A fusion gene is formed by t(9;11)(p21.
3;q23.
3) chromosome translocation.
Among them, lysine methyltransferase 2A or KMT2A (formerly known as MLL) gene mutation is more important in AML.
Common, the incidence is about 10% [7], of which KMT2A and MLLT3 (also known as AF9 or LTG9) gene fusion is the most common type
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Compared with other types of AML with KMT2A fusion gene, the prognosis of AML with MLLT3-KMT2A fusion gene is significantly different, so it is listed separately [8,9]
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Previous studies have shown that the MLLT3-KMT2A fusion gene is related to the occurrence of monocyte phenotype of AML, and it has the characteristics of rapid disease progression, high recurrence rate and short survival period [10,11]
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ELN 2017 guidelines list AML positive for the MLLT3-KMT2A fusion gene as an intermediate risk group
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Previous studies have shown that the median OS of AML with positive MLLT3-KMT2A fusion gene is 11.
3 months, and the recurrence-free survival period is about 9.
5 months
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At the same time, it was found that there were more cases of combined KRAS or NRAS mutations (36%), and fewer cases of combined FLT3 mutations (8%).
Whether combined with RAS or FLT3 mutations, the patient's OS would be reduced
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This conclusion indicates that the activation of the Ras pathway may play a complementary role with MLLT3-KMT2A in tumorigenesis, but this conclusion remains to be confirmed [12]
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6DEK-NUP214 The DEK-NUP214 fusion gene is caused by t(6;9)(p22.
3;q34.
1), which is related to about 1% of AML occurrence [13]
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The study by Carl Sandén et al.
found that the DEK-NUP214 gene mainly affects the process of cell proliferation.
It promotes cell proliferation by up-regulating the activity of rapamycin complex 1 (mTORC1).
Treatment with rapamycin receptor inhibitors can inhibit such The proliferation of leukemia cells has a certain effect [14]
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DEK-NUP214 fusion gene-positive AML usually has a poor prognosis.
A cohort study conducted by Slovak showed that the CR rate of this type of AML (including children and adults) is only 65%, the median OS is only 13.
5 months, and the median DFS is only 9.
9.
Months
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Because this type of AML responds poorly to chemotherapy, allogeneic hematopoietic stem cell transplantation is the treatment of choice
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According to the pairing study done by K Ishiyama et al.
, it is compared with normal karyotype AML treated by HSCT under the same conditions (including gender, age, CR, pretreatment plan, blood donors, HLA mismatch number, etc.
) AML with EK-NUP214 fusion gene positive has no significant difference in OS, DFS, etc.
The 5-year OS rate is about 45%, the 5-year DFS rate is about 40%, and the 5-year total recurrence rate is about 42%
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However, due to the insufficient number of people included in the study, this conclusion has yet to be confirmed [15]
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The 7KMT2AKMT2A gene (also known as the MLL gene), located at 11q23, encodes histone H3 lysine 4 methyltransferase
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KMT2A gene rearrangement occurs in about 3%-7% of adults with first-onset AML [16]
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KMT2A encodes a histone methyltransferase, which plays a major role in maintaining gene expression during embryonic development and hematopoiesis
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KMT2A gene translocation will produce a chimeric KMT2A fusion protein, which directly binds to DNA and up-regulates gene transcription, resulting in abnormal expression of downstream KMT2A targets, including HOX genes, which leads to the occurrence of AML [16]
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The study of Y Chen et al.
showed that the total CR rate of AML with KMT2A gene mutation was 68%, and the median OS was 8.
5 months
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The 5-year survival rate of AML patients with KMT2A gene mutations in the non-MLLT3-KMT2A group is only 0-18%, and the 5-year EFS rate is only 0-6%
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Patients who received allogeneic hematopoietic stem cell transplantation after CR had better OS and recurrence-free survival (RFS) than patients who received chemotherapy only [17]
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The study of Marius Bill et al.
also showed that AML with KMT2A gene mutations in the non-MLLT3-KMT2A group was poor in CR rate, 3-year DFS rate and median OS [18]
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To be continued, I will introduce the relationship between several AML gene mutations and prognosis
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In the next issue of "The Relationship between Several Gene Mutations in Acute Myeloid Leukemia and Prognosis (Part 2)", the exciting continues, so stay tuned! References: [1]OPATZ S, BAMOPOULOS SA, METZELER KH, et al.
2020.
The clinical mutatome of core binding factor leukemia.
Leukemia [J], 34: 1553-1562.
[2]GAIDZIK VI, BULLINGER L, SCHLENK RF, et al.
2011.
RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group.
J Clin Oncol [J], 29: 1364-1372.
[3]EM Heath,SM Chan, MD Minden,T Murphy,LI Shlush,AD Schimmer.
Biological and clinical consequences of NPM1 mutations in AML[J].
Leukemia,2017,31(20):[4]DUPLOYEZ N, WILLEKENS C, MARCEAU-RENAUT A, et al .
2015.
Prognosis and monitoring of core-binding factor acute myeloid leukemia: current and emerging factors.
Expert Rev Hematol [J], 8: 43-56.
[5]DOHNER H, ESTEY E, GRIMWADE D, et al.
2017.
Diagnosis and management of AML in adults:
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Medical expertise: More than 20 years of clinical medical work in internal medicine and hematology
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For many years, he has been engaged in the research of leukemia cell apoptosis signal transduction mechanism and molecular targeted therapy of hematological tumors
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Proficient in diagnosis and treatment of various anemias, bleeding diseases and hematological tumors
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Diagnosis and treatment of diseases including hematopoietic stem cell transplantation, leukemia chemotherapy, malignant lymphoma and multiple myeloma and other individualized treatment options for malignant hematological diseases, various unexplained anemia, unexplained long-term fever, and differential diagnosis of lymphadenopathy and treatment
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