T cell-acute lymphocytic leukemia molecular genetic changes and new advances in targeted therapy

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T cell- acute lymphocytic leukemia (T-ALL)

T-cell acute lymphocytic leukemia (T-ALL) is a highly progressive malignant hematological tumor with a poor prognosis and high recurrence rate. Especially in adult T-ALL patients, only 40% of survival can exceed 5 years .

In recent years, the use of gene expression chips and next-generation sequence analysis technology to further understand the genetic changes of many important genes during the development of T-ALL and its main molecular mechanism in the malignant transformation of T cells has been used to predict the prognosis of the disease And targeted therapy research is of great significance. This article mainly introduces the research progress of T-ALL molecular genetics at the 54th annual meeting of the American Society of Hematology (ASH) in 2012 and its clinical significance in diagnosis and treatment.

Characteristics of early pre-T cell acute lymphoblastic leukemia (ETP-ALL)

In 2009, Campana et al. described a new T-ALL subtype. This type of T-ALL originated from early thymocytes with multi-lineage differentiation potential and was called ETP-ALL. ETP-ALL cells express cytoplasmic CD3 but not CDta and CD8, weakly express or not express CD5, abnormally express stem cells and myeloid markers, with myeloid-like gene alteration characteristics (such as high frequency FLT3 mutations) The immunophenotype and transcription characteristics of early T precursor cells (differentiation plasticity) in mice are similar.

However, ETP-ALL cells lack T-ALL gene alteration characteristics, such as NOTCH1 activating mutations and CDKN2A / B deletions, and also lack the common chromosomal rearrangement of T-ALL.

ETP-ALL accounts for 10% to 15% of children and adults with ALL, and the difference in frequency is mainly related to the different diagnostic immunophenotype standards adopted by different research centers. The poor prognosis of ETP-ALL is associated with poor treatment response, failure of induction therapy, and short disease-free survival.

Different research groups have recently analyzed the molecular genetic changes of ETP-ALL through new-generation sequence analysis and other technologies, and have roughly discovered the following genetic characteristics:

(1) ETP-ALL is common in three signal pathway gene mutations, including hematopoietic development, RAS and (or) cytokine receptor / JAK-STAT signal transduction, and histone modification signal pathway. 58% of ETP-ALL contains some developmental genes, including RUNX1, IKZF1, ETV6, GATA3 and EP300 loss-of-function mutations, and the frequency of these molecular genetic changes in non-ETP-ALL is 17%.

Activating gene mutations can be found in 67% of ETP-ALL patients, including NRAS, KRAS, JAK1, NFI, PN11, JAK3, SH2B3 (encoding LNK, a negative regulator of JAK2 signal transduction) and new mutations of IL7R In non-ETP-ALL, the frequency of these changes is only 19%.

(2) Adult ETP-ALL molecular genetic changes have high heterogeneity, and there are high mutations of apparent regulatory factors. The frequency of DNA methyltransferase gene DNMT3A (DNA-methyl-transferase 3A) mutations is higher ( 16%), common mutations also include PRC2 (D0lycomb repressor complex 2) components, a class of H3K27 trimethylases that induce normal transcriptional suppression and counteract the transcriptional activation effect of MLL. The most common mutant gene in PRC2 is EZH2 (The catalytic component that encodes the complex) EZH2 mutations can also occur in follicular lymphoma, but the functioning Y641 mutation occurs, and in T-ALL, the EZH2 mutation occurs at other sites, such as where research predicts that it destroys the catalytic SET region and renders it non-functional.

Another study on the detection of gene mutations in ETP-ALL-PRC family members showed that EZH2 mutations were found in 4 of 68 cases, SUZ12 mutations were found in 1 of 68 cases, and SH2B3 gene mutations were found in 4 of 69 cases. , Patients with mutations in at least one apparent regulator gene (DNMT3A, SUZ12, SH2B3, MLL2, or EZH2) showed poor survival tendency (1-year survival rate: 50% to 85%, P = 0.08).

(3) The frequency of GATA3 expression loss in ETP-ALL is very high (11/17), but it is very low in other T-ALLs (3/69). 26% (19/71) of the ETP-ALL is GATA3, while only 2% (2/94) of the T-ALL belongs to the GATA3 group. At the same time, GATA3 in the ETP-ALL cells is hypermethylated (28% methylated) CpG), therefore, GATA3 expression loss is associated with gene silencing caused by hypermethylation. In addition, in ETP-ALL, DNMT3A loss-of-function mutation is associated with GATA3 hypomethylation.

In general, these new research results clearly describe the molecular genetic changes of ETP-ALL. In addition to clarifying that ETP-ALL may represent a characteristic of stem cells or leukemia precursor cells, it can further clarify the prognosis and disease of the disease. Design corresponding targeted therapy studies.

For example, the loss of GATA3 expression is associated with gene silencing caused by hypermethylation, and the DNMT3A loss-of-function mutation is associated with GATA3 hypomethylation. Therefore, the characteristic of DNMT3A apparent silencing in GATA3 is worth taking advantage of, because the drugs targeted for T ALL Limited, combined demethylation drugs may solve the problem of inducing T cell differentiation and blocking T-ALL by increasing GATA3 expression. In addition, the characteristics of DNMT3A high mutations suggest that epigenetic regulation may be a therapeutic target.

TAL1 research progress and its application value

TAL1, also known as SCL, is a transcription factor with oncogene characteristics. T-AL1 was first discovered at the translocation break point of chromosome t (1; 14) (p32; ql1) in T-ALL patients. This translocation concatenates the TAL1 gene on chromosome 1 with the T cell receptor 8 site on chromosome 14 to cause ectopic expression of TAL1.

Subsequently, different fusion genes involving the TAL1 locus were found in some T-ALLs. At the same time, some human T-ALLs (40%) without chromosomal translocation also showed abnormal expression of TAL1, which is a main feature of T-ALL. .

TAL1 can induce T-ALL in a mouse model. Later studies further identified TAL1 as an important hematopoietic transcription factor, which plays an important role in the regulation of hematopoietic development. At this ASH annual meeting, some studies further clarified the regulatory mechanism of TAL1 activation in T-ALL, mainly involving epigenetic regulatory mechanisms.

Kang et al. studied how TAL1l is activated in most T-ALLs lacking TAL1 site rearrangement. They found that a TIL16 (TAL1 interacting locus in chromosome 16) element can bind to the TAL1 promoter 1a and activate TAL1. To T cell specific enhancer effect, this effect is related to the H3K4 trimethylation of TIL16.

Another study showed that miR-223 is a physiological target of TAL1 during normal thymus development. The expression of miR-223 in TAL1-positive cell lines is significantly higher than that of TAL1 low-expression cell lines, and forced expression of miR-223 can be partially restored The growth inhibition of T-ALL caused by TAL1 knockout, and the inhibition of mature miR-223 by miR-223 shRNA can significantly inhibit the growth of TAL1 positive cells and induce apoptosis.

The effect of MiR-223 on TAL1 is related to the regulation of FBXW7 tumor suppressor gene expression. These results show the new apparent regulation mechanism caused by abnormal activation of TAL1 oncogene in T-ALL, and also provide some alternative new targets for targeted inhibition of T-ALL.

NOTCH1 related genes and their targeted regulation

NOTCH1 plays an important role in the development and differentiation of normal T cells. Activated NOTCH1 mutations occur in 50% -60% of T-ALL. Activated NOTCH1 can positively regulate mTOR activity and enhance PI3K / Akt by down-regulating the expression of PTEN signal transduction.

Previous studies have used NO
TCH1 as an important target for the treatment of T-ALL. Clinical trials have shown that NOTCH1 inhibitors can reduce and eliminate some leukemia-initiating cells (L-IC) in T and ALL, but due to obvious Intestinal toxicity, clinical application of anti-NOTCH1 therapy is limited.

Therefore, searching for molecules associated with NOTCH1 to explore more specific or synergistic targets is the focus of recent research, and some new results have also been reported at this ASH annual meeting.

C-myc inhibitor

c-myc is an oncogene closely related to the occurrence and development of T-ALL, and is a direct transcription target molecule of NOTCH signal. In primary mouse T-ALL cells, silencing c-myc can significantly prolong survival by reducing the number of L-ICs and self-renewal ability.

A new domain (bromodomain) inhibitor JQ1 can prolong the survival of mice T-ALL, at least in part by reducing c-myc mRNA and protein levels, but its therapeutic effect on T-ALL patients needs to be further the study.

3.2 Synergy of NOTCH and PI3K / mToR signaling pathway inhibitors

In I’ALL with abnormal NOTCH signals, targeted inhibition of PI3K / mTOR can increase NOTCH-MYC activity. Therefore, when using PI3K inhibitors to treat T-ALL and other NOTCH signal-activated malignancies, two considerations The rationality of the combined use of pathway drugs, PI3K / roTOR dual inhibitor PI-103 combined with NOTCH inhibitor GSI (small molecule-secretase inhibitor), or PI-103 combined with c-myc inhibitor 1 0058-F4 can be significantly reduced Proliferation of T-ALL cells.

Targeted inhibition of ZMIZ

ZMIZ is a possible synergistic factor of NOTCH. It is a STAT-activated protein inhibitor (activated STAT, PIAS) -like family member transcription joint activator. It shares a zinc finger zone (MIZ zone) with PIAS protein.

In the mouse model, the synergy between ZMIZ1 and leukemia-related NOTCH1 alleles promotes T-ALL formation. In a subset of T-ALL patients, ZMIZ1 and activated NOTCH1 are co-expressed. Gene-level inhibition of ZMIZ1 can delay leukemia cell growth and overcome the resistance of some T-ALL cell lines to NOTCH inhibitors.

Targeted inhibition of RUNX

Studies have been conducted to clone the insertion site from 88 primary mouse leukemias in a model of relatively weakly activated NOTCH1 transgenic mice to induce leukemia, and to identify synergistic molecules outside the NOTCH pathway through the retrovirus insertion mutation screening method Mutation, in which the insertion region with a higher frequency is at RUNX3, and the binding region of RUNX3 is a 40-60 kb region tightly clustered upstream of the transcription start position. It is speculated that the retroviral LTR may induce an increase in RUNX3 expression. And a single binding region upstream of RUNX1 is also a region with a higher frequency of mutations.

In addition, most studies show that RUNX1 and RUNX3 are widely expressed in T-ALL samples. Silencing T using lentiviral shRNA After RUNX1 and / or RUNX3 of ALL cells, the growth of T-ALL cells is inhibited, and G-phase cells are significantly reduced.

In contrast, overexpression of RUNX3 induced rapid proliferation of T-ALL cells and produced resistance to ABT-263-induced apoptosis. NOTCH1 and RUNX factors regulate the expression of surface proteins IGF1R and IL7R in a synergistic or superimposed manner, and IGF1R and IL7R play an important role in the growth of T-ALL cells and the activity of leukemia-initiating cells, which shows a development in T-ALL The mechanism of synergy between the new NOTCH1 and RUNX proteins.

Another study clarified at the genomic level how NOTCH works with other transcription factors in human and mouse T-cell leukemia / lymphoma (T-LL) to regulate the transcriptome of T-LL cells (transcriptome), found the relationship between NOTCH1, RBPJ, ETS1, GABPA and RUNX1 each factor binding site, NOTCH1 / RBPJ and ETS1 / GABPA and RUNX1 factor binding sites have many overlaps, combined application of ETS or RUNX1 silencing and GSI treatment, the cell Apoptosis and growth inhibitory effect is more obvious than the drug alone.


In the process of using zebrafish to screen small molecule drugs against MYC overexpressing thymocytes and human T-ALL cell lines in vitro to screen for drugs that synergistically interact with NOTCH inhibitors, one drug that fits the two screens is haloperidol (perphenazine), an antipsychotic drug approved by the US FDA.

Hydrochlorpromazine has the effect of inducing mitochondrial apoptosis and anti-leukemia activity in zebrafish T-ALL, human T-ALL cell lines and primary T-ALL cells. The analysis of the drug and its binding target was carried out by proteomics method of binding activity It was found that protein phosphatase 2A (protein phosphatase 2A, PP2A) is the target of the anti-leukemia effect of haloperidol.

Hydrochlorpromazine has the effect of activating PP2A in T-ALL cells, which can be simulated by FTY720, a known PP2A activator. Silencing PP2A branches or catalytic subunits with shRNA can weaken the activity of haloperidol, suggesting that PP2A is necessary for the anti-leukemia effect of haloperidol.

This study shows that the pharmaceutical activation of the tumor suppressor PP2A is a therapeutic strategy. At the same time, the occurrence of tumors may also be caused by excessive phosphorylation of PP2A substrates, which also points out some new treatments for T-ALL Ideas.


Early research found that KLF4 (Krtippel like factor 4) restricts the proliferation of normal CD8 + T cells. KLF4 deletion can increase the self-renewal of normal hematopoietic stem cells and enhance survival. This is a feature that tumor cells need to obtain during the transformation process. .

KLF4 expression was reduced in bone marrow samples of T-ALL patients, and KLF4 expression was related to the response of ALL patients to standard treatment. After inserting the NOTCH1 mutant of human T-ALL cells (NOTCH1-L1601P-DP mutation) into mouse KLF4 deletion and KLF4 wild-type bone marrow cells respectively, the results after transplantation into mice showed: KLF4 deletion bone marrow cell mouse leukemia incidence significantly increased, the survival period was shortened.

This study shows that KLF4 plays a role as a tumor suppressor in the NOTCH1-induced T-ALL model, providing a new molecular target for preventing the growth of leukemia cells.

Prognosis related genes

In recent years, studies on predicting the prognosis of the disease at the genetic level and defining different subgroups of leukemia have had an important impact on clinical treatment. Using a new generation of sequence analysis technology to identify the new genetic changes in T-ALL found that older male children have a tendency to find high signs.

Therefore, some studies have performed sequencing analysis on the exome of the x chromosome gene, and found that the frequency of deletion mutations of PHF6 is very high. PHF6 encodes a possible zinc finger transcription factor-PHD zinc finger protein 6, but PHF6 changes The significance of T cell leukemia needs to be further clarified. Some reports on the prognostic evaluation of T-ALL at the genetic level at this ASH annual meeting are recommended.

Most previous studies have shown that bcr-abl-negative T-ALL with NOTCH1 and / or FBXW7 mutations has a significant beneficial effect on treatment, and the lack of NOTCH1 and / or FBXW7 mutations is associated with poor prognosis. But there are still 1/3 of T-AI | lJ with NOTCH1 and / or FBXW7 mutation recurrence, therefore, to determine a very favorable prognosis, it needs to be further defined.

A multi-center randomized clinical trial (GRAALL-2003, 2005) of 212 adult T-ALL samples showed that the favorable prognosis of NOTCH1 and / or FBXW7 mutations is limited to those without K-RAS / PTEN abnormalities, so , Suggest a new low-risk T-ALL oncogene classification that is accompanied by NOTCH1 and / or FBXW7 mutations but not RAS / PTEN mutations (51% in this group of study samples),
while 49%), including 13% of NOTCH1 and / or FBXW7 mutations and those with RAS / PTEN mutations, belong to the high-risk group.

This result proves that the detection of RAS and PTEN increases the important prognostic value of evaluating the mutation status of NOTCH1 and / or FBXW7, and it can be further found that nearly 50% of adult T-ALL have a very good prognosis.

In addition, in a group of 53 initial T-ALLs treated according to a unified protocol (pre-T-ALL 28 cases, cortical / mature T-ALL 25 cases), aCGH (oligonucleotide array comparative genomic hybridization) Phenotype markers and gene mutations (including the common oncogenes NOTCH1, IL7R, FLT3, NRAS and tumor suppressor genes FBXW7, PTEN, DNM2, PHF6, BCL11B, WT1, EZH2, ETV6, IDH1, IDH2, DNMT3A , GATA3, RUNX1, etc.) comprehensive analysis of molecular-level prognostic indicators.

The results showed that the pre-T-ALL gene expression characteristics were related to hematopoietic stem cells and myeloid progenitor cells, and were related to poor prognosis and short overall survival time; CD13 + was significantly related to poor survival; most (22 cases) pre-T-ALL were accompanied by TCR Bi-allelic deletion. In children’s T-ALL, this molecular marker is also associated with poor overall survival; loss of heterozygosity on the short arm of chromosome 17 (including TP53) predicts the worst clinical effect.

The homozygous CDKN2A / CDKN2B deletion of the short arm of chromosome 9 is associated with favorable prognosis (but the favorable prognosis of CDKN2A / CDKN2B homozygous deletion is limited to mature T-ALL patients); NOTCH1 and / or FBXW7 mutations lead to activation; the NOTCH1 signal is associated with favorable prognosis; BCL11B heterozygous inactive mutations or deletions also belong to the type of favorable prognosis; the apparent regulatory genes DNMT3A and IDHI / 2 mutations are associated with disease progression.

In general, in adult T-ALL, multivariate analysis shows that the most important association is that NOTCH1 and / or FBXW7 mutations are associated with favorable prognosis, TP53 deletion and DNMT3A mutation are associated with poor prognosis, and more importantly, the homozygous CDKN2A / CDKN2B deletion and CD5 may be used as prognostic markers for the further stratification of mature T ALL in adults, and the DNMT3A mutation has the value of risk stratification for high-risk early immature T-ALL.

At the moment, genomic sequence analysis research is mostly focused on figuring out what kinds of changes happen to somatic genes that code for proteins. It has become clearer what molecular genetic changes are important for figuring out T-ALL risk and treatment targets.

It is also very important to identify the role of all genetic changes in the development of leukemia and determine the role of non-coding genetic changes in the development of leukemia. The new generation of sequence analysis has brought a wealth of information, and the detailed molecular mechanism of disease development means that further understanding will be more significant for clinical diagnosis and treatment.

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