Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity.

Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rß and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue-programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase-mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3-IL-10-producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF-producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ T memory progenitor cells are enriched with anti-IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti-IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.

Plasma fibronectin can affect the cytokine profile and monocytes/macrophages function in addition to predicting the prognosis of advanced sepsis.

The value of plasma fibronectin (pFN) in the diagnosis and prognosis of sepsis has not been fully established. Previous studies finding that pFN is significantly reduced in sepsis, however, whether reduced pFn affects the prognosis of sepsis has not been clarified. Here, we detected and analyzed pFN and other conventional inflammatory markers in advanced sepsis patients and performed correlation analysis with SOFA score. We also used Fn gene conditional knockout mice which were performed by cecum ligation and puncture (CLP) to investigate the effect of FN deficiency on sepsis prognosis. We found, compared with procalcitonin, c-reactive protein, and interleukin-6, pFN was more correlated with SOFA score in advanced sepsis patients (r -.720, p < .001). In animal experiments, Fn gene knockout mice showed significantly greater mortality after CLP compared with the control group because of inhibited phagocytosis and bacterial clearance ability of macrophages, with double cytokine storm. Furthermore, FN can regulate macrophages through the integrin α5ß1/Fak/Src signaling pathway. Overall, we found pFN can more accurately reflect the severity and prognosis of advanced sepsis. The absence of FN altered the cytokine storm and phagocytic function of macrophages, suggesting that FN could be a potential therapeutic target in sepsis.

A novel prognostic nomogram for adult acute lymphoblastic leukemia: a comprehensive analysis of 321 patients.

The cure rate of acute lymphoblastic leukemia (ALL) in adolescents and adults remains poor. This study aimed to establish a prognostic model for ≥14-year-old patients with ALL to guide treatment decisions. We retrospectively analyzed the data of 321 ALL patients between January 2017 and June 2020. Patients were randomly (2:1 ratio) divided into either the training or validation set. A nomogram was used to construct a prognostic model. Multivariate Cox analysis of the training set showed that age > 50 years, white blood cell count > 28.52×109/L, and MLL rearrangement were independent risk factors for overall survival (OS), while platelet count >37×109/L was an independent protective factor. The nomogram was established according to these independent prognostic factors in the training set, where patients were grouped into two categories: low-risk (≤13.15) and high-risk (>13.15). The survival analysis, for either total patients or sub-group patients, showed that both OS and progression-free survival (PFS) of low-risk patients was significantly better than that of high-risk patients. Moreover, treatment analysis showed that both OS and progression-free survival (PFS) of ALL with stem cell transplantation (SCT) were significantly better than that of ALL without SCT. Further stratified analysis showed that in low-risk patients, the OS and PFS of patients with SCT were significantly better than those of patients without SCT. In contrast, in high-risk patients, compared with non-SCT patients, receiving SCT can only significantly prolong the PFS, but it does not benefit the OS. We established a simple and effective prognostic model for ≥ 14-year-old patients with ALL that can provide accurate risk stratification and determine the clinical strategy.

Homoharringtonine potentiates the antileukemic activity of arsenic trioxide against acute myeloid leukemia cells.

Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3ß (GSK3ß). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.

Identification and functional characterization of voltage-gated sodium channels in lymphocytes.

A variety of ion channels has been discovered in lymphocytes. RT-PCR and real-time PCR analysis revealed that ALL (acute lymphocytic leukemia) cell lines and human peripheral blood mononuclear cells mainly expressed TTX (tetrodotoxin)-sensitive voltage-gated sodium channels (VGSCs). Expression of VGSC protein was confirmed by western blots and Immunofluorescence. Whole-cell patch-clamp recordings showed that a sub-population (20%) of MOLT-4 cells expressed functional VGSCs, which were TTX-sensitive. Importantly, 2 µM TTX decreased the invasion of Jurkat and MOLT-4 cells ∼90%. These results indicate that the activity of VGSCs could represent a novel mechanism potentiating the invasive capacity of these cells.

Bone marrow stromal cells protect acute myeloid leukemia cells from anti-CD44 therapy partly through regulating PI3K/Akt-p27(Kip1) axis.

The anti-CD44 monoclonal antibody (mAb) A3D8 induces differentiation or apoptosis in vitro in various subtypes of acute myeloid leukemia (AML) via p27(Kip1) upregulation. Bone marrow (BM) stromal cells play a vital role in the development of chemoresistance in AML cells attached to the stroma. To investigate the effect of BM stroma adhesion induced AML resistance to A3D8, we developed a co-culture system composed of an AML-derived cell line (NB4) cultured with either a human BM stroma cell line (HS-5) or mesenchymal stem cells (MSCs). We found that NB4 cells adhered to HS-5 cells or MSCs developed resistance against the anti-proliferative effects of A3D8, and this action is caused by the activation of PI3K/Akt signaling following p27(Kip1) down-regulation and cytoplasmic re-localization. The stromal co-culture-induced resistance can be partially abolished by inhibiting the PI3K/Akt signaling pathway. Such findings were confirmed in two additional AML-derived cell lines as well as in primary AML cells. Our results suggest that BM stroma can induce A3D8 resistance in part via the PI3K/Akt-p27(Kip1) axis, and blocking PI3K/Akt pathway maybe necessary for anti-CD44 treatment on AML in BM microenvironment.

Knockdown of Adhesion-Regulating Molecule 1 Inhibits Proliferation in HL60 Cells.

BACKGROUND/AIMS: Adhesion-regulating molecule 1 (ADRM1), a receptor located on the 26S proteasome, is upregulated in many solid cancers. However, little is known about its role in acute leukemia (AL). METHODS: We determined ADRM1 expression levels in both untreated AL samples and leukemia cell lines using real-time polymerase chain reaction or Western blot analysis. Growth curves, colony formation assays, cell cycle and apoptosis analyses, cell migration and invasion assays and NF-κB p65 nuclear translocation assays via Western blotting were used to examine the biological behavior of HL60 cells and the underlying mechanism. RESULTS: ADRM1 was upregulated in both untreated AL samples and leukemia cell lines. ADRM1 knockdown significantly suppressed HL60 cell proliferation (48.82 ± 12.58%) and colony formation and caused cell cycle arrest in the G0/G1 phase. Furthermore, we confirmed that ADRM1 knockdown suppressed p65 nuclear translocation. CONCLUSION: Our study revealed that ADRM1 was overexpressed in AL, especially in CD34+ leukemia stem and progenitor cells. ADRM1 may play a role in AL via the proteasome-ubiquitin pathway by potentially sustaining the activation of NF-κB signaling.

Role of Ets-1 in fibronectin-derived heparin-binding domain polypeptides alleviating melanoma cell invasiveness and chemoresistance.

In this study, we observed that rhFNHN29 and rhFNHC36, two recombinant heparin-binding domain polypeptides of fibronectin, suppressed adhesion and invasion of B16F10 and A375 melanoma cells mediated by integrin αv and α2 in a dose-dependent manner. Combined with low-concentration epirubicin (EPI), rhFNHN29 or rhFNHC36 exhibited a synergistic inhibition on the viability and metastasis of B16F10 cells. Moreover, in the presence of high-concentration rhFNHN29 or rhFNHC36, the Ets-1 activity and the expression of p-FAK, p-Erk1/2 and Ets-1 were notably downregulated in B16F10 cells. Ets-1 is one of the central regulatory links for rhFNHN29 and rhFNHC36 to suppress the adhesion and invasion of melanoma cells. Combining rhFNHN29 or rhFNHC36 with EPI may be a good way to alleviate invasiveness or chemoresistance in melanoma.

Loss of B7-H1 expression by recipient parenchymal cells leads to expansion of infiltrating donor CD8+ T cells and persistence of graft-versus-host disease.

Previous experimental studies have shown that acute graft-versus-host disease (GVHD) is associated with two waves of donor CD8(+) T cell expansion. In the current studies, we used in vivo bioluminescent imaging, in vivo BrdU labeling, and three different experimental GVHD systems to show that B7-H1 expression by recipient parenchymal cells controls the second wave of alloreactive donor CD8(+) T cell expansion and the associated second phase of GVHD. Loss of B7-H1 expression by parenchymal cells during the course of GVHD was associated with persistent proliferation of donor CD8(+) T cells in GVHD target tissues and continued tissue injury, whereas persistent expression of B7-H1 expression by parenchymal cells led to reduced proliferation of donor CD8(+) T cells in GVHD target tissues and resolution of GVHD. These studies demonstrate that parenchymal cell expression of B7-H1 is required for tolerizing infiltrating T cells and preventing the persistence of GVHD. Our results suggest that therapies designed to preserve or restore expression of B7-H1 expression by parenchymal tissues in the recipient could prevent or ameliorate GVHD in humans.

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro.

AIM: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. METHODS: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. RESULTS: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC50 at low micromole levels. C817 (0.5 or 1 µmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. CONCLUSION: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.

The effect to IL-3Ralpha, downstream PI3k/Akt signaling of all-trans retinoic acid and arsenic trioxide in NB4 cells.

All-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are the classic drugs used for induction therapy of acute promyelocytic leukemia (APL). IL-3Ralpha (CD123) is a specific marker of acute myeloid leukemia stem cells (AML-LSCs). The over-expression of IL-3Ralpha in patients with AML is related to high white blood cells counts, high percentages of blast cells, and poor prognosis. Moreover, in some studies, IL-3Ralpha has been considered a new detection marker of minimal residual disease in the bone marrow from patients with APL. In contrast to ATRA, As2O3 reduces both mRNA and protein expression of IL-3Ralpha and inhibits the activity of PI3K/Akt after 24 h, 48 h, and 72 h of exposure. Furthermore, NB4 cells adhered to the human stroma cell line HS-5 cells were used as an in vitro model of APL cells in the bone marrow microenvironment. Our results demonstrate that adhesion to HS-5 cells up-regulated IL-3Ralpha protein expression and activated the downstream PI3K/Akt signaling pathway in NB4 cells. Compared with ATRA, As2O3 more potently inhibits proliferation of NB4 cells adhered to stroma cells.

[The Effect of TCP1 Expression on the Proliferation and the Accumulation of Intracellular Drug of HL60/A and HL60 Cell and Its Mechanism].

OBJECTIVE: To investigate the effect of TCP1 expression on the proliferation and the accumulation of intracellular drug of HL60/A and HL60 cells and its possible molecular mechanism. METHODS: Lentiviral transfection technology was used to construct HL60/A and HL60 cells with knocked down or overexpressed TCP1 and their control cells. The efficiency of knockdown and overexpression was evaluated by Western blot. The cell proliferation was detected by CCK-8 assay. The intracellular drug accumulation was detected by laser confocal detection and flow cytometry. The expression levels of MRP1, P-gP and p-AKT were evaluated by flow cytometry and Western blot. RESULTS: After TCP1 was knocked down,the proliferation ability of HL60/A cells was significantly reduced, the accumulation of intracellular drug was significantly increased and the expression of MRP1 and P-gP protein were decreased. After TCP1 was overexpressed, the proliferation ability of HL60 was significantly increased, the accumulation of intracellular drug was significantly decreased and the expression of MRP1 and P-gP protein were increased. Intervention of LY294002 significantly antagonized the promotion on cell proliferation, the inhibition on intracellular drug accumulation and the expression of MRP1 and P-gP mediated by TCP1 overexpressing in HL60 cells. CONCLUSION: TCP1 can promote cell proliferation, improve the expression of MRP1 and P-gP by activating PI3K/AKT signal, and reduce intracellular drug accumulation.

Non­m6A RNA modifications in haematological malignancies.

Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N6-methyladenosine (m6A) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-m6A RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the m6A modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-m6A RNA modifications. In this review, we mainly focus on the roles and implications of non-m6A RNA modifications, including N4-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N1-methyladenosine and N7-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-m6A RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-m6A RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-m6A modifiers in blood cancer.

Bovine serum albumin-based probe carrier platform for electrochemical DNA biosensing.

A bovine serum albumin (BSA)-monolayer-based probe carrier platform is shown to improve the performance of a conventional thiolated single-stranded DNA probe self-assembled-monolayer-based electrochemical DNA hybridization biosensor. A detection limit of 0.5 fM can be obtained in a very reproducible manner (relative standard deviation <5%), along with high specificity. The performance of the biosensor can be attributed primarily to the enhanced spatial positioning range and accessibility of the probes on the BSA-based platform. Furthermore, the novel biosensor shows high resistance to nonspecific adsorption of nucleic acid and protein and can be directly employed in detection in biological fluids. These advantages give this simple developed methodology great promise for a wide range of nucleic acid testing.

Population genetic analyses of the STR loci of the AmpFlSTR NGM SElect™ kit for Han population in Fujian Province, China.

Allele frequencies and forensically relevant population statistics of the STR loci in the AmpFlSTR® NGM SElect™ PCR Amplification Kit were estimated for the Han population from Fujian province in China (n = 454). All loci were highly polymorphic and the cumulative match probability was 5.4 × 10(-21). No significant departure from Hardy-Weinberg equilibrium and linkage equilibrium was detected after correction for sampling. The population substructure of Fujian Han population is minor.

Sequence-specific electrochemical detection of double-strand PCR amplicons of PML/RARα fusion gene in acute promyelocytic leukemia.

A novel electrochemical method for the sequence-specific detection of double-stranded polymerase chain reaction (PCR) products of PML/RARα fusion gene in acute promyelocytic leukemia (APL) was described in detail. Based on a "sandwich" sensing mode involving a pair of locked nucleic acids probes (capture probe and reporter probe), this DNA sensor exhibited excellent selectivity and specificity. The direct and quantitative analysis of double-stranded complementary was firstly performed by our sensor without the use of alkali, helicase enzymes, or denaturants. Finally, combining PCR technique with electrochemical detection scheme, PCR amplicons (191 bp) of the PML/RARα fusion gene were obtained and rapidly identified with a low detection limit of 79 fmol in the 100-µL hybridization system. The results clearly showed the power of sensor as a promising tool for the sensitive, specific, and portable detection of APL and other diseases.

C-Terminal Fibronectin Exerts Beneficial Effects in Reducing Tissue Damage and Modulating Macrophage Function in a Murine Septic Model.

Background: Fibronectin (FN) can improve organ function and slow the progression of sepsis, but full-length FN is hard to be exacted as a therapeutic. Objective: This study aimed to investigate the beneficial effects of C-terminal heparin-binding domain polypeptide of FN (rhFNHC-36) in a cecal ligation and puncture (CLP)-mediated murine septic model and explore its regulatory effects on macrophages. Methods: Mice were randomly assigned to four groups: unoperated control (Normal), sham operation control (Sham), CLP-operation with intravenous injection of phosphate-buffered saline (CLP+PBS), and CLP-operation with rhFNHC-36 treatment (CLP+rhFNHC-36). Blood and abdominal fluid samples were subjected to bacterial colony formation assays. Organs (liver, spleen, and lung) were undergone histopathological analyses and/or weighed to obtain organ indices. Serum interleukin-6 (IL-6) levels, nitric oxide (NO) release from isolated abdominal macrophages, and chemotactic effect of macrophages were measured with commercial kits. Surface programmed death ligand 1 (PD-L1) expression on macrophages was measured by flow cytometry. Results: Mice in the CLP+PBS group showed a lower survival rate than that in the CLP+rhFNHC-36 group. Improved survival was associated with better clearance of bacterial pathogens, as evidenced by colony formation assays. The CLP-induced decrease in thymus and spleen indices was attenuated by rhFNHC-36 treatments. rhFNHC-36 alleviated sepsis-associated tissue damage in liver, spleen, and lung. CLP-mediated increases in plasma IL-6 levels were reversed by rhFNHC-36 treatment. NO levels in peritoneal macrophages after lipopolysaccharides (LPS)-stimulation in the CLP+rhFNHC-36 group were lower than that in the CLP+PBS group. Notably, macrophages from the CLP+rhFNHC-36 group retained better chemotaxis ability. After LPS challenge, these macrophages had a reduced percentage of PD-L1-positive cells compared to those in the CLP+PBS group. Conclusion: rhFNHC-36 improved survival of mice with CLP-induced sepsis by reducing tissue damage and modulating macrophage function. Our work provides critical insight for developing FN-based and macrophages-targeted therapeutics for treating sepsis.

Application of G-CSF in high-leukocyte acute myeloid leukemia is a poor prognostic factor.

OBJECTIVE: To analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML). METHODS: A total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L. RESULTS: The application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes. CONCLUSIONS: G/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.

Molecular beacon-based fluorescence biosensor for the detection of gene fragment and PCR amplification products related to chronic myelogenous leukemia.

A novel fluorescence method has been established for the determination of gene fragment and PCR amplification products related to chronic myelogenous leukemia (CML). A molecular beacon (MB) which comprises a DNA loop section, a pair of fluorophore (tetramethoxyl rhodamine, TAMRA), and a quencher (4-(2-methyl-on-amino-azobenzene) benzoate, DABCYL) was designed. The loop sequence of MB was designed according to the DNA sequence relating to CML (type b3a2) which contained a single-stranded oligonucleotide. Before hybridization, the fluorescence from the TAMRA had been quenched by the DABCYL. After hybridization with the complementary DNA, the quencher will become far away from the TAMRA, and the fluorescence intensity detected will increase. Changes in the fluorescence intensity have a linear relationship with the concentration of complementary DNA (C) in the range of 4.0 × 10(-9)-3.2 × 10(-8) mol/L, with a correlation coefficient of 0.9973; the detection limit was 6.0 × 10(-10) mol/L (S/N = 3). The developed method has high selectivity, which can be used to discriminate single-base mismatch sequence. The method has been applied to detect the short-stranded CML DNA fragment (278 bp) with high sensitivity. This approach is a promising method for the detection of CML in real samples for medical diagnostics.

Tyrosine kinase inhibitors and reduced-dose chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

Objectives: To compare the outcomes of tyrosine kinase inhibitors (TKIs) in combination with reduced-dose chemotherapy with those of standard induction chemotherapy, as well as the outcomes between chemotherapy and transplantation, in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).Methods: We retrospectively reviewed cases of Ph+ ALL treated with TKIs and combination chemotherapy. The patients were allocated to either the TKIs with reduced-dose chemotherapy group or the TKIs with standard chemotherapy group. In additions, patients were further stratified into either the transplant group or the non-transplant group.Results: The complete remission rate (88.7% vs. 83.9%, p = 0.372), major molecular response (58.9% vs. 56.0%, p = 0.750), molecular complete response (20.5% vs. 22.0%, p = 0.891), and early mortality rate (3.2% vs. 3.5%, p = 0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infections, bloodstream infections, patients with >21 days of hospitalization, the total costs, transfusion costs, and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates (59.0% [95% CI, 46.6-74.7%] vs. 38.4% [95% CI, 29.9-49.4%]) and disease-free survival rates (48.6% [95% CI, 34.2-69.1%] vs. 32.0% [95% CI, 23.5-43.7%]) were significantly better in the transplant group than in the non-transplant group.Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation during the first complete remission remains a suitable and effective option for patients with Ph+ ALL.