Correction: Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Correction to:Signal Transduction and Targeted Therapy(2022)7:1–13,https://doi.org/10.1038/s41392-021-00870-3 In the original version of this article,given name of 4th author Yannan Jia was incorrectly published as Yanan Jia.The original article has been corrected.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source.

Treatment of STAT5b-RARA positive acute promyelocytic leukemia by Venetoclax combining with homoharringtonine, cytarabine: A case report and literature review

Introduction:Acute promyelocytic leukemia(APL)is mostly due to the chromosome translocation t(15;17)(q22;q12),leading to the formation of PML-RARA fusion protein.Some patients carried rare translocation involving RARA gene,who were called variant APL caused by RAR family(RARA,RARB,and RARG)and partner genes.STAT5b-RARA was a rare type of molecular genetic abnormality with unfavorable prognosis which have been reported in only 18 cases in variant APL.Knowledge of STAT5b-RARA(+)APL treatment is still limited.Case report:We presented a 38-year-old female variant APL case,who was STAT5b-RARA positive detected by reverse transcription polymerase chain reaction.The patient failed to respond after four-drug combined induction chemotherapy:idarubicin,cytarabine,all trans retinoic acid,and arsenic trioxide(As 2 O 3).Then,the patient was re-induced with azacytidine,but still failed to achieve complete remission(CR).Next,she was treated with Venetoclax combining with homoharringtonine and cytarabine as the salvage therapy and achieved CR.Later,the patient received hematopoietic stem cell transplantation after 4 cycles of consolidation therapy.Conclusion:Venetoclax combining with homoharringtonine and cytarabine has been used as the salvage therapy in the STAT5b-RARA positive APL successfully.

Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.

Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia

Methotrexate(MTX)has an antitumor effect when used for the treatment of acute lymphoblastic leukemia(ALL).This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX.Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay.The serum MTX concentration was determined using homogeneous enzyme immunoassay.MTX-related toxicities were also evaluated.Renal toxicity was significantly associated with higher serum MTX concentrations at 24,48,and 72 hours,and MTX elimination delay(P=0.001,P<0.001,P<0.001,and P<0.001,respectively),whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours,and MTX elimination delay in candidate polymorphisms(P=0.014,P=0.019,and P=0.007,respectively).SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours(P=0.016,P=0.043,respectively).MTRR rs1801394 was associated with serum MTX concentrations at 72 hours(P=0.045).Neutropenia was related to SLC19A1 rs4149056(odds ratio[OR]:3.172,95%confidence interval[CI]:1.310–7.681,P=0.011).Hepatotoxicity was associated with ABCC2 rs2273697(OR:3.494,95%CI:1.236–9.873,P=0.018)and MTRR rs1801394(OR:0.231,95%CI:0.084–0.632,P=0.004).Polymorphisms of SLCO1B1,SLC19A1,ABCC2,and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.

Mature plasmacytoid dendritic cells associated with acute myeloid leukemia show similar genetic mutations and expression profiles to leukemia cells

Introduction:Mature plasmacytoid dendritic cells(pDCs)proliferation associated with myeloid neoplasms(MPDMN)are recognized as a neoplasm related to fully differentiated pDCs.Although it has been reported for many years,the genomic landscape of MPDMN is poorly understood.Methods:We reported two patients who developed acute myeloid leukemia(French-American-British M5 subtype)coexisted with immunophenotypically mature pDCs proliferation,which fit the diagnosis of MPDMN.We sorted pDCs from myeloid blasts by flow cytometry and performed whole-exome sequencing and RNA sequencing of the two cell populations,respectively.Results:The immunophenotypes of pDCs in both patients were positive for CD123bri,HLA-DR,CD4,CD303,CD304,and negative for CD56,CD34,CD117,and TdT.The variant allele frequency of gene mutations in myeloid blasts and pDCs were similar.The expression data showed myeloid blasts clustered tightly with hematopoietic stem cells,and pDCs from patients clustered tightly with granulocyte-monocyte progenitors/common myeloid progenitor,rather than with pDCs from the GEO platform.Conclusion:Our study suggested that pDCs derived from the leukemic clone,evidenced by a shared mutation profile and similar transcriptional signatures between pDCs and concurrent myeloid blasts.

The impact of venetoclax based regimens in the preemptive of measurable residual disease in acute myeloid leukemia

To The Editor:The role of measurable residual disease(MRD)in prognosis and treatment in acute myeloid leukemia(AML)is evolving.Studies have demonstrated the correlation between MRD and risks of relapse in adult AML:persistently positive MRD after induction is associated with a high risk of relapse,1,2 and these patients should consider allogeneic transplantation(allo-Hematopoietic Stem Cell Transplantation(HSCT))and clinical trial,even in favorable-risk groups.However,because of the financial issue or lack of suitable transplant donors,many of the patients could not receive allo-HSCT,so how to prolong the relapse-free survival of these patients remains a challenge.Platzbecker et al treated MRD-positive patients with azacytidine(AZA),and found pre-emptive therapy with AZA can prevent or substantially delay hematological relapse in MRD-positive patients with MDS(myelodysplastic syndrome)or AML who are at a high risk of relapse.

Heterogeneity analysis of the CEBPAdm AML based on bZIP region mutations

Patients with double-mutated CEBPA(CEBPAdm)AML were stratified into favorable risk group,however,few studies have investigated the heterogeneity of different CEBPAdm types in detail.In this study,we analyzed 2211 newly diagnosed AML and identified CEBPAdm in 10.8%of the patients.Within the CEBPAdm cohort,225 of 239 patients(94.14%)presented with bZIP region mutations(CEBPAdmbZIP)while 14 of 239 patients(5.86%)without bZIP region mutation(CEBPAdmnonbZIP).Analysis of the accompanied molecular mutations showed statistically different incidences of GATA2 mutations between the CEBPAdmbZIP group and the CEBPAdmnonbZIP group(30.29%vs 0%).In the analysis of outcomes,patients with CEBPAdmnonbZIP were associated with shorter overall survival(OS)censored at hematopoietic stem cell transplantation(HSCT)during CR1 compared to those with CEBPAdmbZIP(hazard ratio(HR)=3.132,95%confidence interval(CI)=1.229–7.979,P=.017).Refractory or relapsed AML(R/RAML)patients with CEBPAdmnonbZIP were associated with shorter OS compared to those with CEBPAdmbZIP(HR=2.881,95%CI=1.021–8.131,P=.046).Taken together,AML with CEBPAdmbZIP and CEBPAdmnonbZIP showed different outcomes and might be regarded as distinctive AML entities.

CACA guidelines for holistic integrative management of adult acute myeloid leukemia

The CACA Guidelines was summarized by Hematology Oncology Committee of China Anti-Cancer Association.This portion of the CACA Guidelines for adult acute myeloid leukemia(AML)not only focuses on diagnosis,the treat-ment options for younger(age<60 years)and older(age≥60 years)patients(including non-APL,APL,R/R AML),but also pay attention to the treatment of AML complications,including central nervous system leukemia(CNSL),cardiotoxicity,agranulocytosis and fever,hepatitis B virus reactivation,uric acid nephropathy,bleeding and coagula-tion disorders,and nursing for patients with AML from the perspective of holistic integrative medicine to enhance the quality of life and treatment effects.