The relationship between several gene mutations and prognosis in acute myeloid leukemia (part 2)

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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In the last article, we introduced the relationship between the 7 gene mutations of AML and the prognosis [please click for details: the relationship between several gene mutations in acute myeloid leukemia and the prognosis (on)], today, let’s take a look at the other 6 The relationship between AML gene mutation and prognosis! 8BCR-ABL1 BCR-ABL1 positive (ie, Philadelphia chromosome positive) AML is a very rare type with an incidence of less than 1% [19]
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This type of AML usually has a poor prognosis and was included in the high-risk group in the 2017 ELN guidelines
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It is also very different from other types of AML treatment options.
It usually requires early application of TKI.
Studies have shown that early acceptance of allogeneic hematopoietic stem cell transplantation can improve the prognosis.
After hematopoietic stem cell transplantation, the 5-year survival rate of patients can reach 53.
8%.
The 5-year recurrence rate was 37%, and the DFS rate was 44.
2% [20]
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9GATA2, MECOMGATA2, MECOM are produced by inv(3)(q21q26.
2)/t(3;3)(q21;q26.
2), and the incidence in AML is about 1-2%[21]
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The mechanism leading to AML is related to the relocation of the GATA2 enhancer near the stem cell regulator ecological virus integration site 1 (EVI1) gene, which leads to the overexpression of this gene [22]
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GATA2, MECOM gene positive AML has a very low OS rate and a poor prognosis
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Foreign studies have shown that the 5-year survival rate of this type of AML patients is extremely low (OS: 5.
7% ± 3%; EFS: 0%; RFS: 4.
3% ± 4%) [23]
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Other studies have shown that even after hematopoietic stem cell transplantation, the 1-year and 4-year OS rates of such patients are only 41% and 13% [21]
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The 10RUNX1RUNX1 (Runt-related transcription factor 1) gene is located on chromosome 21q22.
Studies have shown that the incidence of this gene mutation in AML is approximately 13% [24]
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RUNX1 is responsible for encoding the ɑ subunit in CBF (core binding factor), and CBF plays an important role in the hematopoiesis process, so mutations in the RUNX1 gene can lead to the occurrence of AML
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In AML, chromosomal translocations involving RUNX1 include t(8;21)(q22;q22); RUNX1-RUNX1T1; t(3;21)(q26.
2;q22); and EVI1-RUNX1
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Among them, AML positive for the RUNX1-RUNX1T1 fusion gene usually has a better prognosis
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The 2017 ELN specifically pointed out that if the RUNX1 gene mutation is combined with the gene mutation of the good prognosis group, it should not be classified into the poor prognosis group
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Studies have shown that patients with RUNX1 mutations have a worse prognosis and a lower survival rate than patients with non-RUNX1 mutations
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The estimated 4-year survival rate for patients with RUNX1 mutant AML is as follows: EFS rate is 8%, RFS rate is 26%, and OS rate is 32%
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In patients with normal karyotype acute myeloid leukemia (CN-AML), RUNX1 mutations have worse EFS than non-RUNX1 mutations, but no difference was found in RFS and OS.
The estimated 4-year EFS rate is 10% [24]
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Other related studies also support this view [25]
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The 11ASXL1ASXL1 (additional comb-like 1) gene is located on chromosome 20q11, and the ASXL1 gene mutation has a higher incidence in AML, about 5%-11%[26]
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Studies have shown that wild-type ASXL1 plays an important role in maintaining normal hematopoietic function
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Loss of ASXL1 results in the hindrance of the differentiation of progenitor cells and leads to the development of myeloid malignancies
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Most ASXL1 mutations are heterozygous frameshift or nonsense mutations located near the 5'end of the last exon.
This mutation is generally considered to be a loss-of-function mutation.
However, there are also studies that show that the c-terminal truncation caused by the ASXL1 mutation ASXL1 protein can induce myeloid transformation, leading to the occurrence of AML [27]
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Mutations in ASXL1 are often associated with poor prognosis
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The 2017 ELN guidelines specifically pointed out that if the ASXL1 gene mutation is combined with a gene mutation in the good prognosis group, it should not be classified into the poor prognosis group
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Compared with wild-type ASXL1 patients, patients with ASXL1 mutations have lower CR rates, EFS rates and OS rates
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Studies have shown that in the moderate and poor-risk AML group, patients with ASXL1 mutations have shorter OS and DFS than ASXL1 wild-type patients (3-year OS rate: 47.
5% vs 60.
8%; 3-year DFS rate: 28.
5% vs 48.
9%)
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In CN-AML, there are differences in the OS rate (47.
4% vs 65.
2%) and DFS rate (21.
0% vs 52.
1%) between ASXL1 mutant patients and ASXL1 wild-type patients [28]
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The 12TP53TP53 gene is located on chromosome 17.
Although the TP53 gene mutation has a high incidence in solid tumors, its incidence in AML is not high, about 12.
7% [29]
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In AML, TP53 gene mutations will affect the structure, folding and stability of p53 protein, and affect its DNA binding ability and physiological activity
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Some of the TP53 mutations may have loss of function (LOF) and dominant negative effects on the remaining wild-type alleles, while other mutations will lead to the acquisition of functional phenotypes, leading to the formation of tumors
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In AML, TP53 gene mutation is usually associated with poor prognosis.
Studies have shown that the median OS time of AML with TP53 gene mutation is only 9 months [30]
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Other studies have also shown that changes in TP53 are associated with lower survival rates
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The estimated 3-year survival rates of patients with TP53 change and TP53 unchanged are: EFS rate: 1% vs 13%; RFS rate: 7% vs 30%; OS rate: 3% vs 28% [31]
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13FLT3-ITDFLT3 (FMS-like tyrosine kinase 3 gene) belongs to the class III tyrosine kinase receptor family member, located on chromosome 13q12, and encodes a membrane-bound protein
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When the ligand binds to the FLT3 receptor in the extracellular domain, FLT3 dimerizes, thereby mediating a series of intracellular signal transduction and regulating cell differentiation, proliferation and apoptosis
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FLT3 gene mutations are common mutations in AML, including internal tandem duplication (ITD) in the proximal membrane region
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The incidence of FLT3-ITD in AML is approximately 27% [32]
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FLT3-ITD mutation-positive AML patients have the characteristics of easy relapse and short survival time
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Studies have shown that according to a single factor analysis, when comparing the 5-year OS rate, DFS rate, EFS rate, and remission rate, AML patients with FLT3-ITD mutation-positive are worse than FLT3-ITD mutation-negative patients
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Domestic studies have also shown that the number of FLT3-ITD mutations does not affect the prognosis of patients
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The length of FLT3-ITD mutation rearrangement bases also has no significant effect on the prognosis of patients
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The OS and duration of complete remission (CRD) in patients with FLT3-ITD mutation ratio <10% are similar to those in the intermediate-risk group of AML patients with C-KIT mutation in the same period, and they are significantly longer than those in patients with mutation ratio ≥10%
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In patients with FLT3-ITD mutation positive AML (except M3), patients with a FLT3-ITD mutation ratio of <10% have a better prognosis than patients with a mutation ratio of ≥10% [33]
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Summary In summary, genetic changes are closely related to the prognosis of AML, such as RUNX1-RUNX1T1 fusion gene, CBFB-MYH11 fusion gene, NPM1 mutation and FLT3 mutation negative, CEBPA double mutation and good prognosis; FLT3-ITD mutation, ASXL1 gene mutation, RUNX1 Gene mutation, DEK-NUP214 fusion gene, GATA2, MECOM have poor prognosis; MLLT3-KMT2A fusion gene and NPM1 gene mutation and FLT3-ITD high expression are in the middle
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With the advancement of detection technology, it is believed that more genes related to the occurrence of AML will be discovered in the future, and evaluating the impact of these genes on the prognosis is still of great significance in guiding the treatment of AML
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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: 2017 ELN recommendations from an international expert panel.
Blood [J], 129: 424-447.
[6] Zhang Mengna, Yang Yanli, Geng Yinghua, Li Jun, Feng Huixin.
The relationship between CEBPA gene mutation and clinical characteristics and prognosis of acute myeloid leukemia[J].
Journal of Clinical Hematology, 2021, 34 (09):659-663.
[7] Arber DA, Orazi A, Hasserjian R, et al.
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
Blood.
2016;127(20):2391- 2405.
[J].
Blood,2016,128(3):[8] Diagnostic Tool for the Identification of MLL Rearrangements Including Unknown Partner Genes[J].
Proceedings of the National Academy of Sciences of the United States of America,2005, 102(2):[9]C Meyer,E Kowarz,J Hofmann,A Renneville,J Zuna,J Trka,R Ben Abdelali,E Macintyre,E De Braekeleer,M De Braekeleer,E Delabesse,MP de Oliveira,H Cavé , et al New insights to the MLL recombinome of acute leukemias[J].
Leukemia,2009,23(8):[10]De Braekeleer Marc,Morel Frédéric,Le Bris Marie-Josée,Herry Angèle,Douet-Guilbert Nathalie.
The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia.
[J].
Anticancer research,2005,25(3B):[11]Schoch Claudia,Schnittger Susanne,Klaus Mirjam,Kern Wolfgang,Hiddemann Wolfgang,Haferlach Torsten.
AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases[J].
Blood,2003,102(7):[12 ]HEATH EM, CHAN SM, MINDEN MD, et al.
2017.
Biological and clinical consequences of NPM1 mutations in AML.
Leukemia [J], 31: 798-807.
[13]CHANDRA P, LUTHRA R, ZUO Z, et al .
2010.
Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases.
Am J Clin Pathol [J], 133:686-693.
[14]Carl Sanden, Malin Ageberg, Jessica Petersson, Andreas Lennartsson, Urban Gullberg.
FORCED EXPRESSION OF THE DEK-NUP214 FUSION PROTEIN PROMOTES PROLIFERATION DEPENDENT ON UPREGULATION OF MTOR[J].
Inventi Impact Cancer,2014,2014: [15] Díaz-Beyá Marina, Labopin Myriam, Maertens Johan, Alijurf Mahmoud, Passweg Jakob, Dietrich Beelen, Schouten Harry, Socié Gerard, Schaap Nicolaas, Schwerdtfeger Rainer, Volin Liisa, Michallet Mauricette, Polge Emmanadelle, Moherra Mohamorge, Sierra Moherra Esteve Jordi,Nagler Arnon.
Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission.
[J].
British journal of haematology,2020, 189(5):[16]BILL M, MROZEK K, KOHLSCHMIDT J, et al.
2020.
Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.
Proc Natl Acad Sci USA [J], 117: 26340-26346.
[17]Y Chen,H Kantarjian,S Pierce,S Faderl, S O'Brien,W Qiao,L Abruzzo,M de Lima,P Kebriaei,E Jabbour,N Daver,T Kadia,Z Estrov,G Garcia-Manero,J Cortes,F Ravandi.
Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation[J].
Leukemia,2013,27(4):[18]ASADA S, FUJINO T, GOYAMA S, et al.
2019.
The role of ASXL1 in hematopoiesis and myeloid malignancies.
Cell Mol Life Sci [J], 76: 2511-2523.
[19]Arber Daniel A.
,Orazi Attilio,Hasserjian Robert,Thiele Jürgen,Borowitz Michael J.
,Le Beau Michelle M.
,Bloomfield Clara D.
,Cazzola Mario,Vardiman James W.
.
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J].
Blood,2016,127(20):[20]LAZAREVIC VL, LABOPIN M, DEPEI W, et al.
2018.
Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT).
Am J Hematol [J], 93: 31-39.
[21]Marta Sitges ,Blanca Boluda,Ana Garrido,Mireia Morgades,Isabel et al.
Acute myeloid leukemia with inv(3)(q21.
3q26.
2)/t(3;3)(q21.
3;q26.
2): ​​Study of 61 patients treated with intensive protocols[J].
European Journal of Haematology,2020,105(2):[22]Hiromi Yamazaki,Mikiko Suzuki,Akihito Otsuki,Ritsuko Shimizu,Emery H.
Bresnick,James Douglas Engel,Masayuki Yamamoto.
A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression[J].
Cancer Cell,2014,25(4):[23]Lugthart Sanne,Gröschel Stefan,Beverloo H Berna,Kayser Sabine , et al.
Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.
2)/t(3;3)(q21;q26.
2) and various other 3q abnormalities in acute myeloid leukemia.
[J] .
Journal of clinical oncology: official journal of the American Society of Clinical Oncology,2010,28(24):[24]Tang Jih Luh,Hou Hsin An,Chen Chien Yuan,Liu Chieh Yu et al.
AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations[J].
Blood,2009,114(26):[25]Gaidzik Verena I,Bullinger Lars,Schlenk Richard F, et al.
RUNX1 mutations in acute myeloid leukemia:results from a comprehensive genetic and clinical analysis from the AML study group.
[J].
Journal of clinical oncology: official journal of the American Society of Clinical Oncology,2011,29(10):[26]Chou Wen Chien,Huang Huai Hsuan ,Hou Hsin An,Chen Chien Yuan,Tang Jih Luh,Yao Ming,Tsay Woei,Ko Bor Sheng,Wu Shang Ju,Huang Shang Yi,Hsu Szu Chun,Chen Yao Chang,Huang Yen Ning,Chang Yi Chang,Lee Fen Yu ,Liu Min Chih,Liu Chia Wen,Tseng Mei Hsuan,Tien Hwei Fang.
Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations[J].
Blood,2010,116(20 ):[27]Shuhei Asada,Takeshi Fujino,Susumu Goyama,Toshio Kitamura.
The role of ASXL1 in hematopoiesis and myeloid malignancies[J].
Cellular and Molecular Life Sciences,2019,76(13):[28]Lin Yun,Wang Yaping, Zheng Yi, Wang Zechuan, Wang Yanni, Wang Shaoyuan.
Clinical characteristics and prognostic study of adult acute myeloid leukemia patients with ASXL1 mutations.
[J].
Hematology (Amsterdam, Netherlands),2020,25(1):[29]Magali Olivier,Monica Hollstein,Pierre Hainaut.
TP53 Mutations in Human Cancers : Origins, Consequences, and Clinical Use[J].
Cold Spring Harbor Laboratory Press,2010,2(1):[30]Rücker Frank G.
,Schlenk Richard F.
,Bullinger Lars,Kayser Sabine,Teleanu Veronica,Kett Helena, Habdank Marianne, Kugler Carla Maria, Holzmann Karlheinz, Gaidzik Verena I.
, Paschka Peter, Held Gerhard, von Lilienfeld Toal Marie, Lübbert Michael, Fröhling Stefan, Zenz Thorsten, Krauter Jürgen, Schlegelberge alter leukemia in my TP.
with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome[J].
Blood,2012,119(9):[31]A Stengel,W Kern,T Haferlach,M Meggendorfer,A Fasan,C Haferlach.
The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases[J].
Leukemia,2017,31(3): [32]Kottaridis PD,Gale RE,Frew ME,Harrison G,Langabeer SE,Belton AA,Walker H,Wheatley K,Bowen DT,Burnett AK,Goldstone AH,Linch D C.
The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.
[J].
Blood,2001,98 (6):[33]Ding Shasha,Shen Hongjie,Chen Zixing,Chen Suning,Cen Jiannong,Ding Zixuan,He Jun.
The influence of the number, length and level of FLT3-ITD mutations on the prognosis of patients with acute myeloid leukemia[J].
China Hematology Magazine, 2015, 36(06):449-454.
Professor Liu Jiajun, Chief Physician, Doctoral Supervisor, Director of the Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Member of the Anti-Cancer Branch of the European Tumor Association Member of the Chinese Immunization Association Member of the Standing Committee of the Guangdong Medical Industry Association Member of the Guangdong Society of Hematology, etc.
Main research direction: Leukemia cell apoptosis Research on the mechanism of signal transduction, hematopoietic stem cell transplantation, molecular targeted therapy of hematological tumors, gene therapy and new anti-tumor drugs, etc. .

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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