A review of the research progress of leukemia stem cells in acute T lymphoblastic leukemia

Author: Liu Jiajun, Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen
University
Acute T-lymphocytic leukemia (T-ALL) is an early-stage lymphoid tumor consisting mainly of malignant lymphoblastoid cells expressing immature T-cell surface markers.
of hematopoiesis
.

The incidence of T-ALL is lower than that of other types of leukemia, accounting for 15% of all lymphocytic leukemias.
T-ALL can occur in all people, but it is most common in children aged 2 to 5 [1], and the prognosis is closely related to the age of the patient
.

With the application of multi-drug combined intensive chemotherapy regimens, the 5-year event-free survival (EFS) of children with T-ALL has reached 70-75%, the EFS of adults under 60 years old is 30-40%, and the 5-year event-free survival (EFS) of adults over 60 years old EFS is 10%[2]
.

However, the disease is very easy to relapse.
Once relapsed patients are often resistant to chemotherapy, the prognosis is very poor.
20% of children and most adults die of drug-resistant or relapsed disease patients [3]
.

The pathogenesis of T-ALL is mainly due to the abnormality of key proteins that regulate the development and differentiation of T cells caused by gene mutation and/or chromosomal translocation [4], which in turn leads to malignant transformation of leukemia cells [5]
.

More than 50% of T-ALL have genetic alterations in NOTCH1 or genes related to Notch1 signaling, resulting in constitutive activation of the Notch1 pathway [6, 7]
.

More than 70% of T-ALLs have deletions of p16/INK4A and p14/ARF suppressor genes due to deletion of CDKN2A locus (chromosomal band 9p21) [8]
.

In addition, T cell receptor gene rearrangement is also a common genetic abnormality in T-ALL.
The rearrangement of the TCR gene promoter element and other genes in the open structure of the T cell development stage lead to the occurrence of T-ALL, such as TCR and HOX genes, Translocation of LMO gene and TAL gene [9]
.

Other oncogenic transcription factors include c-Myc, nkx2-1, nkx2-2, etc.
Abnormal expression of these regulatory genes leads to blocked T cell differentiation and induces uncontrolled proliferative signals in T-ALL
.

Leukemia stem cells Rudolf Virchow and Julius Cohnheim proposed the concept of cancer stem cells about 150 years ago.
They believed that cancer is caused by the activation of dormant embryonic tissue remnants.
As early as the 1970s, studies showed that only a part of leukemia cells can survive in vitro Proliferation [10-12], with the development of more in vivo and in vitro studies, it has gradually been found that in the entire leukemia cell population, there are some rare cells that have the potential to self-renew, thereby driving the expansion of leukemia clones, thus proposing leukemia Stem cells (leukemia stem cells, LSCs) [13], also known as leukemia initiating cells (leukemia initiating cells, LICs)
.

LSCs share similar characteristics with normal hematopoietic stem cells, but LSCs do not necessarily differentiate into distinct lineages
.

It is generally believed that LSCs, like normal HSCs, produce differentiated progeny progenitor cells that re-differentiate into leukemic blasts that have lost their ability to self-renew
.

But when these progeny cells developed some mechanical defects, they were unable to fully differentiate into morphologically and phenotypically mature cells
.

Thus, these undifferentiated and variable differentiated leukemia cells collectively constitute the leukemia cell population
.

Overall, leukemia stem cells exhibit at least two distinctive features, namely the ability to self-renew to generate more LSCs and the ability to differentiate into progeny with limited self-renewal potential
.

In studies in the field of hematology, LSCs were first isolated in AML, and then LSCs were found in chronic myeloid leukemia [14], B-ALL [15], and T-ALL [16]
.

With the in-depth study of LSC, it is gradually recognized that the number of LSC is very large, and the study by Ailles LE et al.
found that in some cases, there is 1 LSC cell in every 500 cells [17]
.

Even within the same patient, cell subsets of different phenotypes can possess LSC activity [18-20]
.

In addition, some researchers have observed that LSCs show genomic heterogeneity in the same patient in AML, B-ALL, and T-ALL, and evolve in the progression of leukemia [21-24]
.

At present, more and more studies have shown that the initiation, proliferation and survival of LSCs depend on the abnormal activation of self-renewal and pro-survival signaling pathways [25-27]
.

The leukemia cell population involved in regulating LCS in T-ALL is rich in leukemia stem cells, which play an important role in the occurrence, progression and relapse of leukemia
.

Studies have found that there is a common signaling pathway between normal stem cells and cancer stem cells to regulate their self-renewal capacity, and if the regulation is unbalanced, it will promote the development of cancer
.

At present, with the continuous emergence of research results on the maintenance and proliferation of LSCs in human and mouse T-ALL models, as well as on the key signaling pathways involved in regulating self-renewal, we review the signaling pathways related to leukemia stem cells in T-ALL, and summarize Summarize the roles of these signaling pathways in leukemia progression
.

1 NOTCH1 signaling pathway NOTCH signaling pathway is a major regulator of leukemia cell growth and metabolism.
NOTCH1 is a class I transmembrane protein that directly transduces extracellular signals into changes in gene expression, which act as transcriptional activation ligands.
factor [28, 29]
.

Activation of Notch signaling is initiated by the interaction of the N-terminal EGF repeat in the extracellular region of Notch with Delta-Serrate-Lag2 ligands (Delta-like 1, 3 and 4; and Jagged 1 and 2) located on the surface of adjacent cells of
.

Interaction of NOTCH1 receptors with Delta-like and Jagged ligands expressed on adjacent cell surfaces triggers cleavage of the receptor's extracellular domain by ADAM10 metalloprotease, which in turn triggers the γ-secretase complex to dominate the protein in the transmembrane region Hydrolytic cleavage [30-36] activates the cytoplasmic intracellular portion of NOTCH1 (ICN1) to release from the membrane including the RAM (RBP-Jκ-related module) and ANK (ankyrin repeat) domains and translocate to the nucleus , the RAM domain is responsible for binding to the RBPJ DNA-binding protein while activating the expression of target genes by recruiting MAML transcriptional co-activators [37], and the Ank-rin domain is responsible for stabilizing the structure
.

In addition, NOTCH signaling is tightly regulated, and the C-terminal PEST domain is responsible for terminating NOTCH1 signaling through FBXW7-mediated proteasomal ubiquitination degradation [32, 33, 38]
.

 The NOTCH signaling pathway is involved in the regulation of stem cells, and constitutive expression of Notch1 in hematopoietic stem cells produces immortalized and cytokine-dependent cell lines capable of generating cellular progenitors with lymphoid and myeloid characteristics in vivo and in vitro [39]
.

Notch1 signaling pathway is down-regulated and less active in differentiated hematopoietic cells of peripheral lymphoid organs in a study of transgenic Notch1 reporter mice
.

Inhibition of Notch1 signaling results in accelerated differentiation of hscs in vitro and depletion of hscs in vivo, suggesting that the Notch1 pathway is important for maintaining hscs in an undifferentiated state [40]
.

 The abnormal activation mechanism of NOTCH1 in T-ALL can be summarized into two mechanisms, one is the ligand-independent receptor activation pathway, and the other is the signal termination caused by the impaired stability of ICN1
.

The former is mainly due to the destruction of the negative regulatory region (NRR), which loses the function of protecting the extracellular part of the receptor from cleavage by ADAM10 in the absence of ligands, and the ligand-independent activation or hypersensitivity of NOTCH1 signaling leads to the NOTCH1 signaling pathway.
sustained activation [41, 42]
.

The latter is a PEST domain mutation
.

The PEST domain is thought to be a ubiquitinated substrate that regulates ICN degradation and turnover to ensure termination of NOTCH1 signaling
.

The PEST domain is truncated or lost due to allelic frameshifts or nonsense nucleotide substitutions, resulting in premature stop codons in the C-terminal portion of the receptor
.

PEST mutation affects the targeting of FBXW7-mediated proteasomal degradation of ICN1, prolongs the half-life of the intracellular domain, and leads to increased levels of activated NOTCH1[6]
.

About 20% of T-ALLs also have mutations or deletions in FBXW7, an F-box factor that recognizes phosphorylation motifs in the PEST domain of NOTCH1 and directs ICN1 for ubiquitination and subsequent proteasome degradation [7, 43, 44]
.

It has also been shown that these two mechanisms co-occur in about one-fifth of T-ALL cases, such as disruption of the NRR and PEST regions of NOTCH1, or the presence of both NOTCH1 NRR mutations and FBXW7 mutations.
In these cases, cell membrane Ligand-independent NOTCH activation occurs on the cell nucleus, and the degradation of ICN1 in the nucleus is impaired, resulting in extremely high levels of NOTCH1 activity [6]
.

The oncogenicity of NOTCH1 activating mutations is dose-dependent, so when these two mechanisms occur simultaneously, the synergistic effect of the two mutation-driven activation mechanisms results in a significant increase in NOTCH 1 signaling [45]
.

 The Notch1 pathway is required for the maintenance of LSCs both in vitro and in vivo
.

Armstrong F et al serially transplanted human T-ALL primary cells into immunocompromised nod/scid mice and compared the primary cells with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1).
In co-culture, it was found that LSC cells can survive for a long time, which proves that NOTCH signaling pathway plays a role in the self-renewal of LSC [46], Tatarek J et al.
studied the role of Notch1 in LSC function: treatment with γ-secretase inhibitor leukemia mice and assayed for LSC activity, 4 of the 5 treated mice showed significant reduction or elimination of LSC activity with Notch inhibition and prolonged survival, supporting the possibility of Notch1 therapy as an anti-leukemia drug [47] ]
.

 Several target genes of the Notch1 pathway are also involved in the regulation of LSC activity
.

The study by Medyouf H et al.
found that pharmacological inhibition or gene deletion of insulin-like growth factor 1 receptor (IGF1R) prevented the growth of T-ALL cells and inhibited tumor cell activity.
transplantability of LSCs to secondary recipients [48]
.

The study of King B et al.
found that in T-ALL, the expression of c-Myc is related to LSC activity
.

In Notch1-induced T-ALL mice bearing the c-MycGFP fusion allele, a subpopulation of c-MycGFP-positive cells is enriched in LSCs and shows genes similar to embryonic and hematopoietic stem cells in microarray gene expression profiles feature [49]
.

Giambra V et al.
investigated the role of down-regulated protein kinase C theta (PKC-theta) in T-ALL.
Primary T-ALL mice lacking PKC-theta had high LSC activity, while primary T-ALL mice lacked PKC-theta.
Forced expression of PKC-θ in cells inhibits LIC activity, and it was found that NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 inhibits RUNX1, and RUNX1 induces PKC-θ [50]
.

In their study of humanized NOTCH1 monoclonal antibody in the treatment of T-ALL, Ma W et al found that CD34(+) cells from NOTCH1 (mutated) T-ALL samples were more abundant in the hematopoietic niche than NOTCH1 (wild-type) CD34(+) cells ) cells had higher leukemic engraftment and serial engraftment capacity, indicating that self-renewing LSCs were enriched within the NOTCH1(mutated) CD34(+) fraction, whereas treatment with humanized NOTCH1 mAb decreased NOTCH1(mutated) T- The LSC survival rate and self-renewal ability of ALL LSC-transplanted mice, and lead to the depletion of CD34(+)CD2(+)CD7(+) cells with continuous engraftment ability, provide a new direction for the treatment of T-ALL [51]
.

2 PI3K/Akt/mTOR signaling pathway The PI3K/Akt/mTOR signaling pathway is involved in controlling a variety of cellular physiological processes, including proliferation, differentiation, metabolism, autophagy, angiogenesis, exocytosis, and motility [52]
.

Constitutive activation of PI3K/Akt/mTOR signaling predicts poor prognosis in both solid and hematological tumors [53]
.

Upon stimulation by growth factors and/or cytokines, class I PI3Ks catalyze the production of the membrane phospholipid PIP3, which activates a range of downstream targets, including the serine/threonine kinase Akt, which, once activated, phosphorylates multiple targets Point [54]
.

While Akt's action depends on its ability to phosphorylate substrates involved in cell cycle progression, apoptosis, mRNA translation, glycolytic metabolism, and angiogenesis [55], the PI3K/Akt/mTOR signaling pathway is therefore involved in tumorigenesis of multiple key processes [56]
.

mTOR is a serine-threonine kinase involved in the formation of two multi-protein complexes called mTOR complex 1 (mTORC1) and 2 (mTORC2), which regulate cell growth and metabolism through phosphorylation, and are also important for various It can not only integrate cytokine and growth factor signaling of PI3K-AKT pathway, but also integrate WNT signaling pathway through GSK3β
.

Akt activates mTORC1 through PRAS40 and TSC1/2, while the activation mechanism of mTORC2 is unclear, but they depend on the PI3K/Akt signaling pathway [57]
.

 The PI3K/Akt/mTOR signaling pathway is involved in thymocyte differentiation [58], and upregulation of this signaling pathway is a common feature of T-ALL and suggests a poor prognosis [59]
.

Multiple studies have highlighted the importance of PI3K-Akt activation in T-ALL, showing that PI3K-Akt/mTOR inhibitors block T-ALL cell growth and survival
.

Phosphatase and tensin homology deleted on chromosome ten (PTEN) mutation/deletion is very common in cancer patients and is a tumor suppressor with dual phosphatase activity that activates the PI3K/Akt pathway , involved in the occurrence, maintenance and drug resistance of leukemia [60-64]
.

In addition, mutations in PIK3 and Akt [62, 63], activation of PI3K-Akt and Notch in leukemogenesis synergistically, autocrine insulin-like growth factor and receptor (insulin-like growth factor, IGF-1/ Activation of IGF-1R) signaling pathway [48], acquired mutation of IL7Ra [65], etc.
can activate PI3K/Akt/mTOR signaling pathway
.

 The correlation of PI3K/Akt/mTOR signaling pathway with T-ALL LSC was also found in recent studies
.

Rapamycin blocks the mTORC1 signaling pathway by specifically binding to FKBP12 protein, and is a commonly used mTOR inhibitor.
The study of Guo et al.
LSC formation and inhibit the development of T-ALL
.

However, it was also found that rapamycin alone could not inhibit mTOR signaling in the LSC-enriched c-Kit(mid)CD3(+)Lin(-) cell population, nor could it eliminate these cells [66]
.

This also suggests that multiple genetic events collectively contribute to the formation of LSCs in PTEN-deficient mouse T-ALL [67]
.

As downstream targets of PI3K, mTORC1 and mTORC2 also play important roles in the pathophysiology of T-ALL LSCs
.

Hoshii et al.
found that loss of mTORC1 activity caused by Raptor deficiency eradicated T-ALL in a mouse model of the disease, suggesting that mTORC1 plays a critical role in LSC survival [68]
.

In a zebrafish model of T-ALL, Blackburn et al.
found that increased levels of mTORC1 downstream targets, Ser 473 p-Akt and p-70S6K, were associated with increased LSC frequency, and Akt inhibitor MK-2206 or dual PI3K/mTOR inhibition The agent PI-103 can reduce the frequency of LSC and Akt activation can be down-regulated by epigenetic modifying drugs [69]
.

3 Wnt signaling pathway The Wnt signaling pathway is the main mechanism involved in regulating self-renewal activities in tumor and stem cells
.

The Wnt signaling pathway is a signal transduction pathway of a group of multiple downstream channels excited by the binding of the ligand protein Wnt to the membrane protein receptor
.

Through this pathway, extracellular signals are transmitted into cells through the activation of intracellular segments of cell surface receptors
.

In the canonical Wnt pathway, a cascade of signal transduction begins with the secretion of Wnts glycoproteins
.

Wnts are members of a highly conserved 19 ligand family and are involved in further regulating the growth and differentiation of receptor cells [70]
.

The Wnt/β-catenin pathway is one of the Wnt pathways that is blocked by β-catenin when the Wnt protein binds to the N-terminal cellular cysteine-rich domain of the Frizzled (Fz) family of receptors.
Degradation, allowing β-catenin to accumulate in the cytoplasm and translocate to the nucleus, where it acts as a co-activator with transcription factors from the T cell factor/lymphoid enhancer factor (tcf/lef) family through gene transduction and induction of Wnt target genes Such as the transcription of cyclin D1 and c-Myc
.

β-catenin can also recruit other transcriptional co-activators such as BCL9, Pygopus and Parafibromin/Hyrax
.

When Frizzled or lrp-5/6 receptors are not engaged, Wnt signaling is inactive, β-catenin interacts with Axin, adenomatous Escherichia coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α) form a protein complex that degrades β-catenin by targeting ubiquitination for ubiquitination, which is subsequently delivered to the proteasome for digestion [71]
.

 Wnt signaling also plays a role in the self-renewal of stem cells
.

In embryonic stem cells, the activation of WNT-β-catenin signaling pathway is closely related to self-renewal; in induced pluripotent stem cells, activation of the WNT pathway by GSK3β inhibitor can increase the conversion efficiency of iPSCs[72-74]
.

In hematopoietic stem cells, Reya T et al.
found that activation of β-catenin expression kept HSCs in an undifferentiated state and increased their numbers 20- to 48-fold in long-term in vitro culture, while using inhibitors of the Wnt signaling pathway It can lead to the inhibition of HSC growth in vitro and the reduction of recombination in vivo [75]
.

In addition, it was also found that the expression levels of HoxB4 and Notch1 were increased in β-catenin-activated HSCs, and Wnt signaling may cooperate with the HoxB4 and Notch1 signaling pathways to regulate the function of HSCs [76]
.

 In T-ALL, Wnt signaling may contribute to the establishment of leukemia and the self-renewal activity of LSCs
.

Guo Z et al.
studied the relationship between malignant transformation of mouse thymocytes and β-catenin, and the pathway transduced by the active form of β-catenin stimulated thymocytes to produce T-cell leukemia within 60-80 days, suggesting that β-catenin activation May provide a mechanism for the induction of T-ALL
.

This mechanism is independent of Notch1 activation [77]
.

In addition, elevated β-catenin protein levels were observed in both mouse and human T-ALL [78, 79]
.

T-cell factor 1 (tcf-1) is also a key regulator of T-cell malignant transformation and leukemia maintenance
.

Mice with a zero TCF-1 gene background are susceptible to T-cell leukemia and show abnormal upregulation of LEF1 in preleukemic thymocytes and leukemia cells [80]
.

In addition, TCF-1 also acts as a T cell-specific tumor suppressor in both human and mouse models of T-ALL [81]
.

 Wnt signaling also plays an important biological role in LSCs
.

The study by Guo W et al found that LSCs with self-renewal capacity were enriched in the c-Kit(mid)CD3(+)Lin(-) cell subset, in which unphosphorylated β-catenin was significantly increased, when conditionally excised One allele of the β-catenin gene can significantly reduce the incidence of T-ALL caused by PTEN deletion and delay the occurrence of T-ALL, suggesting that activation of the β-catenin pathway may contribute to the formation of LSC populations or Expand [79]
.

Giambra V et al.
probed the activity of endogenous Wnt signaling using a stably integrated fluorescent Wnt reporter gene
.

The study found that active Wnt signaling was restricted to a small volume of leukemia cells within the bulk tumor, a population of leukemia cells rich in LSCs, and that genetic inactivation of β-catenin severely reduced LSC frequency, but the Deletion does not impair the growth or viability of bulk tumor cells [78]
.

Inhibitors of the Wnt signaling pathway can reduce the proliferation of T-ALL cells in vitro and the survival rate of various human T-ALL cell lines.
Pharmacological inhibitors of the Wnt pathway may be used to treat aggressive T-ALL.
It is also suggested from a therapeutic point of view The Wnt signaling pathway is involved in the self-renewal of LSCs
.

4 HIF-1 Signaling Pathway Oxygen is essential for life and an important regulator of cell metabolism, survival and proliferation
.

Hyperoxia induces the formation of reactive oxygen species (ROS), which may lead to genotoxic effects or cell death
.

Conversely, hypoxia may have broad downstream transcriptional effects, such as activation of pro-apoptotic and pro-angiogenic pathways
.

The cellular response to oxygen levels is monitored in part by the transcriptional activity of hypoxia-inducible factors (HIFs), which regulate multiple pro-angiogenic and pro-glycolytic pathways under hypoxic conditions
.

 HIF is a highly conserved heterodimer composed of two subunits (α and β), the α subunits (HIF-1α, HIF-2α, HIF-3α) are sensitive to high concentrations of oxygen, and only under hypoxic conditions stable down
.

The beta subunit, known as HIF-1β or the aryl hydrocarbon receptor nuclear translocator, is constitutively expressed and is not affected by oxygen levels
.

It is currently believed that HIF regulation is mostly controlled by the alpha subunit, while the beta subunit is insensitive to oxygen levels and constitutively present in the nucleus
.

The HIF1α subunit is a basic helix-loop-helix protein whose structure and function are evolutionarily conserved between mice and humans [82]
.

Under normoxic conditions, HIF-1α undergoes hydroxylation by oxygen-sensitive HIF-1α-specific prolyl hydroxylases (PHD1-3)
.

Hydroxylation triggers polyubiquitination of HIF-1α, resulting in proteasomal degradation of HIF-1α by the E3 ubiquitin ligase-von Hippel-Lindau protein (pVHL) complex
.

Hypoxia inhibits the activity of HIF proline hydroxylase, which uses oxygen as a co-substrate to stabilize HIF-1α, allowing transcriptional activation of HIF-1α target genes
.

 In solid cancers, hypoxia is often present throughout the tissue due to disorganized vascular architecture and areas of necrosis
.

In these regions, the hypoxic state fluctuates in a spatial and temporal manner
.

Transient hypoxic cycles lead to increased activity of HIF proteins above those typical of non-pathological tissues
.

The degree of hypoxia is closely related to poor patient survival, treatment resistance, and aggressive tumor phenotype, and the survival, self-renewal, and tumor growth of cancer stem cells are critically dependent on HIF [83, 84] In hematopoietic stem cells, hypoxia-inducible factors are Regulates transcriptional activity and then participates in regulating the self-renewal and differentiation of hematopoietic stem cell subsets
.

Given that HSCs and progenitor cells exhibit hypoxic characteristics and strongly express HIF-1α, it is speculated that HSCs and progenitor cells exist in a hypoxic bone marrow microenvironment.
It plays an important role in maintenance and leukogenesis [85]
.

 In a mouse model of chronic myeloid leukemia, deletion of HIF-1α in bcr-abl-expressing LSCs reduces the leukogenic activity of LSCs after transplantation into a second recipient and induces p16 (Ink4a) and p19 (Arf) expression, affects cell survival and promotes apoptosis [86]
.

In acute myeloid leukemia, HIF-1α is overexpressed and selectively activated in a CD34+CD38-LSC-enriched subset, and additional pharmacological inhibition of HIF-1α affects transplantation of human LSCs into immunocompromised mice portability in [87, 88]
.

In a NOTCH1-induced mouse T-ALL model, LSC-enriched cell subsets and Wnt signaling-active cell subsets preferentially reside in hypoxic niches in vivo, and stable HIF-1α can be directly upregulated at the transcriptional level Expression of β-catenin, thereby enhancing Wnt signaling, in addition to HIF-1α deletion in mouse leukemia and inhibition of HIF in patient-derived T-ALL xenografts reduces LSC frequency, suggesting that HIF and Wnt/β-catenin Signaling pathways cooperate to support the function of LSCs in T-ALL [78]
.

Other studies have confirmed that the HIF signaling pathway is also closely related to the Notch1 signaling pathway
.

Jie Zou et al.
proposed that the Notch1 signaling pathway is required for hypoxia/HIF-1α-induced T-ALL proliferation, invasion and chemoresistance [89]
.

They found that hypoxia/HIF-1α-activated Notch1 signaling alters the expression of cell cycle regulatory proteins and accelerates cell proliferation, and hypoxia-induced Notch1 activation increases the expression of matrix metalloproteinase 2 (MMP2) and MMP9, thereby increasing invasiveness
.

Wang Y et al.
also demonstrated the important function of HIF-1α-Notch interaction in maintaining LSCs [87], and they found that HIF-1α maintains mouse lymphoma CSCs by inhibiting the negative feedback loop in the Notch pathway
.

The NOTCH pathway and Wnt/β-catenin signaling pathway mentioned above are both important regulatory pathways in leukemia stem cells
.

HIF-1α inhibitors have also become a potential therapeutic direction for T-ALL
.

The current hypothesis for the occurrence of leukemia is that leukemia is a leukemia clone generated by a small fraction of LSCs and maintains the disease.
Through our review, we found that multiple signaling pathways are involved in regulating the self-renewal of LCSs in T-ALL
.

These signaling pathways may not be sufficient by themselves to initiate the leukemia program, but targeted therapy for LCS in disease relapse may offer new directions for patients who are resistant to conventional therapies, and the targets of targeted therapy of LCS exist in these regulators in the signal network of the LCS
.

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Expert Profile 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 Oncology Association, Member of the Chinese Association for Immunology, Member of the Standing Committee of the Guangdong Medical Industry Association, Member of the Guangdong Hematology Association, etc.
Apoptosis signal transduction mechanism, hematopoietic stem cell transplantation, molecular targeted therapy of hematological tumors, gene therapy and mechanism research of new anti-tumor drugs, etc.

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Medical expertise: more than 20 years in the clinical work of internal medicine 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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Skilled in diagnosis and treatment of various anemia, bleeding disorders and hematological tumors
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Diagnosis and treatment of diseases include hematopoietic stem cell transplantation for hematological diseases, leukemia chemotherapy, individualized treatment options for malignant hematological diseases such as malignant lymphoma and multiple myeloma, various unexplained anemias, unexplained long-term fever and differential diagnosis of lymphadenopathy and treatment,
etc.

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