BACKGROUND Acute myeloid leukemia(AML)is one of the most common types of leukemia in adults.However,AML is relatively rare in the population overall,accounting for only about 1 percent of all cancers.Treatment for AML...BACKGROUND Acute myeloid leukemia(AML)is one of the most common types of leukemia in adults.However,AML is relatively rare in the population overall,accounting for only about 1 percent of all cancers.Treatment for AML can be very effective for some patients,yet it leaves others with serious and even life-threatening side effects.Chemotherapy is still the primary treatment for most AML,but over time,leukemia cells become resistant to chemotherapy drugs.In addition,stem cell transplantation,targeted therapy,and immunotherapy are currently available.At the same time,with the progression of the disease,the patient may have corresponding complications,such as coagulation dysfunction,anemia,granulocytopenia,and repeated infection,so transfusion supportive therapy will be involved in the overall treatment regime.To date,few articles have reported on blood transfusion treatment options for patients with ABO subtypes AML-M2.Blood transfusion therapy is an important supportive treatment for AML-M2,and accurate determination of patients'blood type is one of the most important steps in the treatment process.In this study,we explored blood typing and supportive treatment strategies for a patient with A2 subtype AML-M2 to provide the basis for treatment for all patients.CASE SUMMARY In order to determine the blood type of the patient,serological and molecular biological methods were used for reference tests,and the genetic background was studied to determine the patient's final blood type and select the appropriate blood products for infusion treatment.According to the results obtained by serological and molecular biological methods,the blood type of the patient was A2 subtype;the genotype was A02/001;the irregular antibody screening was negative,and anti-A1 was found in the plasma.According to the overall treatment plan,active anti-infection,elevated cells,component blood transfusion support,and other rescue and supportive treatments were given,and the patient successfully passed the stage of myelosuppression after chemotherapy.Re-examination of bone marrow smears showed that AL was in complete remission of bone marrow signs,and minimal residual leukemia lesions suggested no cells with obvious abnormal immunophenotype(residual leukemia cells<10-4).CONCLUSION The infusion of patients with A2 subtype AML-M2 with A irradiated platelets and O washing red blood cells can meet the needs of clinical treatment.展开更多
BACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diag...BACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diagnoses of diffuse large B-cell lymphoma(DLBCL),acute myeloid leukemia(AML),and untreated lymphoplasmacytic lymphoma/Waldenström macroglobulinemia(LPL/WM)in the same patient have not been reported.Here we report one such case.CASE SUMMARY An 89-year-old man had a chest wall mass histopathologically diagnosed as DLBCL.The bone marrow and peripheral blood contained two groups of cells.One group of cells fulfilled the criteria of AML,and the other revealed the features of small B lymphocytic proliferative disorder,which we considered LPL/WM.Multiple chromosomal or genetic changes were detected in bone marrow mononuclear cells,including ATM deletion,CCND1 amplification,mutations of MYD88(L265P)and TP53,WT1 overexpression,and fusion gene of BIRC2-ARAP1,as well as complex chromosomal abnormalities.The patient refused chemotherapy because of old age and died of pneumonia 1 mo after the final diagnosis.CONCLUSION The coexistence of DLBCL,AML,and untreated LPL/WM in the same patient is extremely rare,which probably results from multiple steps of genetic abnormalities.Asymptomatic LPL/WM might have occurred first,then myelodysplastic syndromerelated AML developed,and finally aggressive DLBCL arose.Therefore,medical staff should pay attention to this rare phenomenon to avoid misdiagnoses.展开更多
Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in rec...Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in recent years.Arguably,the most exciting shift has come from the success of treatment with the B-cell lymphoma-2 inhibitor venetoclax.When given in combination with a hypomethylating agent or low dose cytarabine,venetoclax demonstrates high response rates,some of which are durable.In spite of this,relapses after venetoclax treatment are common,and much interest exists in elucidating the mechanisms of resistance to the drug.Alterations in leukemic stem cell metabolism have been identified as a possible escape route,and clinical trials focusing on targeting metabolism in AML are ongoing.This review article highlights current research regarding venetoclax treatment and resistance in AML with a focus on cellular metabolism.展开更多
BACKGROUND Acute myeloid leukemia(AML)harboring 11q23 translocations is classified as therapy-related AML in patients who have undergone prior treatment with cytotoxic agents.There have been only a few reports of AML ...BACKGROUND Acute myeloid leukemia(AML)harboring 11q23 translocations is classified as therapy-related AML in patients who have undergone prior treatment with cytotoxic agents.There have been only a few reports of AML that subsequently developed during imatinib mesylate(IM)treatment for gastrointestinal stromal tumors(GISTs).CASE SUMMARY A 63-year-old woman was diagnosed with a hepatic GIST recurrence in April 2012;she was administered IM 400 mg/d.In November 2015,she developed dyspnea with pancytopenia while IM treatment was continued for 42 mo.A chromosome study using a bone marrow sample showed a 46,XX karyotype with t(11;19)(q23;p13.1)in 22 of 26 analyzed metaphase cells.Fluorescence in situ hybridization using the locus-specific indicator(11q23)gene break-apart probe showed positive rearrangement in 82%of interphase cells.Reverse-transcription polymerase chain reactions subsequently confirmed the KMT2A/ELL transcript.She achieved complete response with incomplete neutrophil recovery with two decitabine treatment cycles.After the third cycle of decitabine,the disease relapsed,and she refused further treatment.She died of hemorrhagic stroke 5 mo after diagnosis.To the best of our knowledge,this is the first report of AML with KMT2A gene rearrangements in a patient with a GIST receiving IM treatment.CONCLUSION Physicians should consider the potential risks of developing hematologic malignancies,including therapy-related AML,in patients with GISTs receiving IM treatment.展开更多
Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of res...Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.展开更多
BACKGROUND Disseminated Fusarium is rare in healthy children.Children with hematological tumors may have secondary fungal infections,including Fusarium infections,which are due to tumor bone marrow infiltration or pro...BACKGROUND Disseminated Fusarium is rare in healthy children.Children with hematological tumors may have secondary fungal infections,including Fusarium infections,which are due to tumor bone marrow infiltration or prolonged bone marrow suppression after chemotherapy.Because of the lack of typical clinical manifestations and effective antifungal drugs,early diagnosis and treatment of the disease are difficult,and the prognosis is poor.CASE SUMMARY The patient in this case was a 13-year-old female child with rash and fever as the first symptoms.She had the characteristics of the four stages of skin that are typical of Fusarium infection.She was diagnosed with disseminated Fusarium infection through skin biopsy and blood culture and diagnosed with Fusarium solani infection based on the morphological characteristics of the blood culture.After treatment with liposome amphotericin B combined with voriconazole,the child recovered.CONCLUSION This case highlights that for children with secondary agranulocytosis after receiving chemotherapy for hematological malignancies,once typical abnormal skin damage is found,the possibility of Fusarium infection should be considered,and voriconazole alone or in combination with polyenes may be the most effective anti-Fusarium drugs.Amphotericin B,the traditional drug of disseminated Fusarium disease,has a high mortality rate,and it is not recommended to use it alone.Adequate neutrophil counts are essential for the treatment of disseminated Fusarium bloodstream infection.展开更多
FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remissio...FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remission rate,patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors(TKIs),such as gilteritinib.And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression.Thus,further investigation is warranted for these FLT3mu,AML patients to achieve a better treatment outcome.4-Hydroxyphenyl retinamide(4-HPR)has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence,with minimal side effects.In this study,we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets.CD34+ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR.Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD.Next,we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD.These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML cells irrespective of stem/progenitor cells or blast cells.4-HPR-induced reactive oxygen species(ROS)production and NF-kB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.展开更多
MDM2 was transfected to acute lymphoblastic leukemia (ALL) line EU-4 cell which lacks P53 expression and expresses very low levels of MDM2. The results showed that MDM2 up-regulated P65 expression in mRNA level and pr...MDM2 was transfected to acute lymphoblastic leukemia (ALL) line EU-4 cell which lacks P53 expression and expresses very low levels of MDM2. The results showed that MDM2 up-regulated P65 expression in mRNA level and protein level. The effect of adriamycin (ADM) on MDM2-transfected EU-4 cell was detected by MTT assay. It was found that MDM2 transfection could increase drug resistance of EU-4 cells to ADM as compared with parent cells. Since the expression of E-selectin is P65 dependent, E-selectin promoter-CAT construct and P65 and MDM2 expression plasmids were co-transfected to EU-4 cells, revealing that MDM2 increased P65-mediated transactivation of E-selectin promoter. In the absence of P65, MDM2 had no effect on the transactivation of E-selectin. Moreover, MDM2 antisense couldn't change the transactivation of E-selectin. It was concluded that MDM2 could up-regulate transcriptionally P65 expression; MDM2 increased drug resistance of leukemia cells to ADM; MDM2 elevated NF-kappaB activity in a P53-independent manner.展开更多
BACKGROUND Rhinocerebral mucormycosis(RCM)is a rare fatal fungal infection which is on the increase among immunocompromised hosts such as patients who have had hematological cancers,or have received immunosuppressive ...BACKGROUND Rhinocerebral mucormycosis(RCM)is a rare fatal fungal infection which is on the increase among immunocompromised hosts such as patients who have had hematological cancers,or have received immunosuppressive drugs,corticosteroids,or other T cell suppressing agents.CASE SUMMARY We report a case of RCM caused by Rhizopus oryzae,one of the most common opportunistic pathogens,in a patient suffering from a fourth relapse of acute myeloid leukemia.The patient developed RCM after he had received long-term antibiotic agents and corticosteroids.The pathogen was isolated three times from nasal secretions collected from the deep parts of the nasal cavity and was identified by morphology and internal transcribed spacer sequencing.Blood infection was excluded by droplet digital polymerase chain reaction and blood culture.The patient was empirically treated with caspofungin and voriconazole for several days while the lesions continued to progress.The patient was given amphotericin B in combination with caspofungin after RCM was suspected,and the lesions improved over the course of treatment,which lasted several days.However,the patient eventually died of the primary disease.CONCLUSION This case indicates that immunosuppressive drugs,including corticosteroids and antimetabolites in hematological tumor,do increase the risk of infections of this type.Early diagnosis,prompt and frequent surgical debridement,and treatment with amphotericin B without delay are all essential in combatting RCM.展开更多
The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use ...The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.展开更多
BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remai...BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.展开更多
Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an in...Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.展开更多
AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assa...AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assays to examine the relation between NF-κB and LIN28 B. Western blot and q RT-PCR was employed to determine their protein and m RNA levels. Luciferase reporter was constructed and applied to explore the transcriptional regulation of LIN28 B. We manipulated LIN28 B level in acute myeloid leukemia(AML) cells and investigated LSC-like properties with colony forming and serial replating assays. RESULTS This study revealed the relationship between NF-κB and LIN28 B in AML cells through drug inhibition and overexpression experiments. Notably,inhibition of NF-κB by pharmacological inhibitors reduced LIN28 B expression and decreased cell proliferation. We demonstrated that NF-κB binds to the-819 to-811 region of LIN28 B promoter,and transcriptionally regulates LIN28 B expression. LIN28 B protein was significantly elevated in NFκB1 transfected cells compared to vector control. Importantly,ectopic expression of LIN28 B partially rescued the self-renewal capacity impaired by pharmacological inhibition of NF-κB activity. CONCLUSION These results uncover a regulatory signaling,NF-κB/LIN28 B,which plays a pivotal role in leukemia stem cell-like properties and it could serve as a promising intervening target for effective treatment of AML disease.展开更多
Macrophages,as a subset of innate immune cells,play a pivotal role in the initiation,maintenance,and resolution of inflammatory responses during tissue damage repair,defense against infections,and tumor progression.Ho...Macrophages,as a subset of innate immune cells,play a pivotal role in the initiation,maintenance,and resolution of inflammatory responses during tissue damage repair,defense against infections,and tumor progression.However,the mechanisms by which macrophages regulate inflammation in acute myeloid leukemia(AML)and their involvement in the chemotherapeutic effect remain elusive.In this study,we have identified that AML cells stimulate macrophage expansion by activating the colony-stimulating factor 1 receptor(CSF1R)pathway.The expanded macrophages activate nuclear factor kappa-B(NFκB)to induce the expression of inflammatory factors,thereby maintaining leukemic cell quiescence and promoting cell survival following chemotherapy.Furthermore,we have successfully utilized a poly(ferulic acid)nanocarrier to selectively target macrophages for inhibiting the NFκB-mediated inflammation,ultimately enhancing chemotherapy efficacy against AML.Taken together,our findings highlight the crucial role of macrophage-induced inflammation in conferring chemoresistance to AML,and demonstrate the potential of a targeted nanocarrier specifically designed for inflammatory macrophages to improve the AML chemotherapeutic outcomes.展开更多
Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin...Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.展开更多
文摘BACKGROUND Acute myeloid leukemia(AML)is one of the most common types of leukemia in adults.However,AML is relatively rare in the population overall,accounting for only about 1 percent of all cancers.Treatment for AML can be very effective for some patients,yet it leaves others with serious and even life-threatening side effects.Chemotherapy is still the primary treatment for most AML,but over time,leukemia cells become resistant to chemotherapy drugs.In addition,stem cell transplantation,targeted therapy,and immunotherapy are currently available.At the same time,with the progression of the disease,the patient may have corresponding complications,such as coagulation dysfunction,anemia,granulocytopenia,and repeated infection,so transfusion supportive therapy will be involved in the overall treatment regime.To date,few articles have reported on blood transfusion treatment options for patients with ABO subtypes AML-M2.Blood transfusion therapy is an important supportive treatment for AML-M2,and accurate determination of patients'blood type is one of the most important steps in the treatment process.In this study,we explored blood typing and supportive treatment strategies for a patient with A2 subtype AML-M2 to provide the basis for treatment for all patients.CASE SUMMARY In order to determine the blood type of the patient,serological and molecular biological methods were used for reference tests,and the genetic background was studied to determine the patient's final blood type and select the appropriate blood products for infusion treatment.According to the results obtained by serological and molecular biological methods,the blood type of the patient was A2 subtype;the genotype was A02/001;the irregular antibody screening was negative,and anti-A1 was found in the plasma.According to the overall treatment plan,active anti-infection,elevated cells,component blood transfusion support,and other rescue and supportive treatments were given,and the patient successfully passed the stage of myelosuppression after chemotherapy.Re-examination of bone marrow smears showed that AL was in complete remission of bone marrow signs,and minimal residual leukemia lesions suggested no cells with obvious abnormal immunophenotype(residual leukemia cells<10-4).CONCLUSION The infusion of patients with A2 subtype AML-M2 with A irradiated platelets and O washing red blood cells can meet the needs of clinical treatment.
基金Supported by the National Natural Science Foundation of China,No.81700130Nanjing Medical University Science and Technology Development Fund.
文摘BACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diagnoses of diffuse large B-cell lymphoma(DLBCL),acute myeloid leukemia(AML),and untreated lymphoplasmacytic lymphoma/Waldenström macroglobulinemia(LPL/WM)in the same patient have not been reported.Here we report one such case.CASE SUMMARY An 89-year-old man had a chest wall mass histopathologically diagnosed as DLBCL.The bone marrow and peripheral blood contained two groups of cells.One group of cells fulfilled the criteria of AML,and the other revealed the features of small B lymphocytic proliferative disorder,which we considered LPL/WM.Multiple chromosomal or genetic changes were detected in bone marrow mononuclear cells,including ATM deletion,CCND1 amplification,mutations of MYD88(L265P)and TP53,WT1 overexpression,and fusion gene of BIRC2-ARAP1,as well as complex chromosomal abnormalities.The patient refused chemotherapy because of old age and died of pneumonia 1 mo after the final diagnosis.CONCLUSION The coexistence of DLBCL,AML,and untreated LPL/WM in the same patient is extremely rare,which probably results from multiple steps of genetic abnormalities.Asymptomatic LPL/WM might have occurred first,then myelodysplastic syndromerelated AML developed,and finally aggressive DLBCL arose.Therefore,medical staff should pay attention to this rare phenomenon to avoid misdiagnoses.
文摘Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in recent years.Arguably,the most exciting shift has come from the success of treatment with the B-cell lymphoma-2 inhibitor venetoclax.When given in combination with a hypomethylating agent or low dose cytarabine,venetoclax demonstrates high response rates,some of which are durable.In spite of this,relapses after venetoclax treatment are common,and much interest exists in elucidating the mechanisms of resistance to the drug.Alterations in leukemic stem cell metabolism have been identified as a possible escape route,and clinical trials focusing on targeting metabolism in AML are ongoing.This review article highlights current research regarding venetoclax treatment and resistance in AML with a focus on cellular metabolism.
文摘BACKGROUND Acute myeloid leukemia(AML)harboring 11q23 translocations is classified as therapy-related AML in patients who have undergone prior treatment with cytotoxic agents.There have been only a few reports of AML that subsequently developed during imatinib mesylate(IM)treatment for gastrointestinal stromal tumors(GISTs).CASE SUMMARY A 63-year-old woman was diagnosed with a hepatic GIST recurrence in April 2012;she was administered IM 400 mg/d.In November 2015,she developed dyspnea with pancytopenia while IM treatment was continued for 42 mo.A chromosome study using a bone marrow sample showed a 46,XX karyotype with t(11;19)(q23;p13.1)in 22 of 26 analyzed metaphase cells.Fluorescence in situ hybridization using the locus-specific indicator(11q23)gene break-apart probe showed positive rearrangement in 82%of interphase cells.Reverse-transcription polymerase chain reactions subsequently confirmed the KMT2A/ELL transcript.She achieved complete response with incomplete neutrophil recovery with two decitabine treatment cycles.After the third cycle of decitabine,the disease relapsed,and she refused further treatment.She died of hemorrhagic stroke 5 mo after diagnosis.To the best of our knowledge,this is the first report of AML with KMT2A gene rearrangements in a patient with a GIST receiving IM treatment.CONCLUSION Physicians should consider the potential risks of developing hematologic malignancies,including therapy-related AML,in patients with GISTs receiving IM treatment.
基金supported by grants from the National Natural Science Foundation of China(Nos.81370660,81170524)
文摘Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.
文摘BACKGROUND Disseminated Fusarium is rare in healthy children.Children with hematological tumors may have secondary fungal infections,including Fusarium infections,which are due to tumor bone marrow infiltration or prolonged bone marrow suppression after chemotherapy.Because of the lack of typical clinical manifestations and effective antifungal drugs,early diagnosis and treatment of the disease are difficult,and the prognosis is poor.CASE SUMMARY The patient in this case was a 13-year-old female child with rash and fever as the first symptoms.She had the characteristics of the four stages of skin that are typical of Fusarium infection.She was diagnosed with disseminated Fusarium infection through skin biopsy and blood culture and diagnosed with Fusarium solani infection based on the morphological characteristics of the blood culture.After treatment with liposome amphotericin B combined with voriconazole,the child recovered.CONCLUSION This case highlights that for children with secondary agranulocytosis after receiving chemotherapy for hematological malignancies,once typical abnormal skin damage is found,the possibility of Fusarium infection should be considered,and voriconazole alone or in combination with polyenes may be the most effective anti-Fusarium drugs.Amphotericin B,the traditional drug of disseminated Fusarium disease,has a high mortality rate,and it is not recommended to use it alone.Adequate neutrophil counts are essential for the treatment of disseminated Fusarium bloodstream infection.
基金This work was partially funded by the National Natural Science Foundation of China(No.81300401)St.Baldrick’s Foundation International Scholar(No.581580)+1 种基金Natural Science Foundation of Guangdong Province(No.2015A030313460)Guangzhou Women and Children’s Medical Center(No.IP-2008-001 and No.GCP-2019-006).
文摘FMS-like tyrosine kinase 3(FLT3)mutation is strongly associated with poor prognosis in acute myeloid leukemia(AML).Though many FLT3 inhibitors have been developed for clinical application with 34%-56%complete remission rate,patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors(TKIs),such as gilteritinib.And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression.Thus,further investigation is warranted for these FLT3mu,AML patients to achieve a better treatment outcome.4-Hydroxyphenyl retinamide(4-HPR)has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence,with minimal side effects.In this study,we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets.CD34+ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR.Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD.Next,we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD.These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML cells irrespective of stem/progenitor cells or blast cells.4-HPR-induced reactive oxygen species(ROS)production and NF-kB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.
基金This project was supported by a grant from National Natu-ral Sciences Foundation of China ( No.3 9970 778)
文摘MDM2 was transfected to acute lymphoblastic leukemia (ALL) line EU-4 cell which lacks P53 expression and expresses very low levels of MDM2. The results showed that MDM2 up-regulated P65 expression in mRNA level and protein level. The effect of adriamycin (ADM) on MDM2-transfected EU-4 cell was detected by MTT assay. It was found that MDM2 transfection could increase drug resistance of EU-4 cells to ADM as compared with parent cells. Since the expression of E-selectin is P65 dependent, E-selectin promoter-CAT construct and P65 and MDM2 expression plasmids were co-transfected to EU-4 cells, revealing that MDM2 increased P65-mediated transactivation of E-selectin promoter. In the absence of P65, MDM2 had no effect on the transactivation of E-selectin. Moreover, MDM2 antisense couldn't change the transactivation of E-selectin. It was concluded that MDM2 could up-regulate transcriptionally P65 expression; MDM2 increased drug resistance of leukemia cells to ADM; MDM2 elevated NF-kappaB activity in a P53-independent manner.
基金National Natural Science Foundation of China,No.81773337Medical and Health Science Technology Project of Shandong Province,No.2017WS345and Traditional Chinese Medicine Science and Technology Development Plans of Shandong Province,No.2017-415.
文摘BACKGROUND Rhinocerebral mucormycosis(RCM)is a rare fatal fungal infection which is on the increase among immunocompromised hosts such as patients who have had hematological cancers,or have received immunosuppressive drugs,corticosteroids,or other T cell suppressing agents.CASE SUMMARY We report a case of RCM caused by Rhizopus oryzae,one of the most common opportunistic pathogens,in a patient suffering from a fourth relapse of acute myeloid leukemia.The patient developed RCM after he had received long-term antibiotic agents and corticosteroids.The pathogen was isolated three times from nasal secretions collected from the deep parts of the nasal cavity and was identified by morphology and internal transcribed spacer sequencing.Blood infection was excluded by droplet digital polymerase chain reaction and blood culture.The patient was empirically treated with caspofungin and voriconazole for several days while the lesions continued to progress.The patient was given amphotericin B in combination with caspofungin after RCM was suspected,and the lesions improved over the course of treatment,which lasted several days.However,the patient eventually died of the primary disease.CONCLUSION This case indicates that immunosuppressive drugs,including corticosteroids and antimetabolites in hematological tumor,do increase the risk of infections of this type.Early diagnosis,prompt and frequent surgical debridement,and treatment with amphotericin B without delay are all essential in combatting RCM.
文摘The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.
文摘BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.
基金Supported by a grant from the Foundation of Ruijin Hospital North Affiliated with Shanghai Jiao Tong University School of Medicine(No.2018ZY03)
文摘Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program to WJ Chng and NMRC Clinician-Scientist IRG Grant CNIG11nov38(Zhou J)supported by NMRC Clinician Scientist Investigator awardpartially supported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 Grants,No.MOE2014-T3-1-006
文摘AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assays to examine the relation between NF-κB and LIN28 B. Western blot and q RT-PCR was employed to determine their protein and m RNA levels. Luciferase reporter was constructed and applied to explore the transcriptional regulation of LIN28 B. We manipulated LIN28 B level in acute myeloid leukemia(AML) cells and investigated LSC-like properties with colony forming and serial replating assays. RESULTS This study revealed the relationship between NF-κB and LIN28 B in AML cells through drug inhibition and overexpression experiments. Notably,inhibition of NF-κB by pharmacological inhibitors reduced LIN28 B expression and decreased cell proliferation. We demonstrated that NF-κB binds to the-819 to-811 region of LIN28 B promoter,and transcriptionally regulates LIN28 B expression. LIN28 B protein was significantly elevated in NFκB1 transfected cells compared to vector control. Importantly,ectopic expression of LIN28 B partially rescued the self-renewal capacity impaired by pharmacological inhibition of NF-κB activity. CONCLUSION These results uncover a regulatory signaling,NF-κB/LIN28 B,which plays a pivotal role in leukemia stem cell-like properties and it could serve as a promising intervening target for effective treatment of AML disease.
基金the National Key Research and Development Program of China(No.2022YFA1103302)the National Natural Science Foundation of China(Nos.92268205,52173150,51973243,82204287)+2 种基金Guangdong Innovative and Entrepreneurial Research Team Program(No.2019ZT08Y485)Guangdong Basic and Applied Basic Research Foundation(No.2021B1515020012)Guangzhou Science and Technology Program City-University Joint Funding Project(No.2023A03J0001).
文摘Macrophages,as a subset of innate immune cells,play a pivotal role in the initiation,maintenance,and resolution of inflammatory responses during tissue damage repair,defense against infections,and tumor progression.However,the mechanisms by which macrophages regulate inflammation in acute myeloid leukemia(AML)and their involvement in the chemotherapeutic effect remain elusive.In this study,we have identified that AML cells stimulate macrophage expansion by activating the colony-stimulating factor 1 receptor(CSF1R)pathway.The expanded macrophages activate nuclear factor kappa-B(NFκB)to induce the expression of inflammatory factors,thereby maintaining leukemic cell quiescence and promoting cell survival following chemotherapy.Furthermore,we have successfully utilized a poly(ferulic acid)nanocarrier to selectively target macrophages for inhibiting the NFκB-mediated inflammation,ultimately enhancing chemotherapy efficacy against AML.Taken together,our findings highlight the crucial role of macrophage-induced inflammation in conferring chemoresistance to AML,and demonstrate the potential of a targeted nanocarrier specifically designed for inflammatory macrophages to improve the AML chemotherapeutic outcomes.
基金supported by grants from the National Natural Science Foundation of China(82074067)Natural Science Foundation of Jiangsu Province China(BK20181419,China)Natural Foundation of Jiangsu Higher Education Institutions of China(19KJA310006)。
文摘Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.
