Network pharmacology to decipher the mechanism of Danggui Longhui Wan against chronic myeloid leukemia

Chronic myeloid leukemia(CML)is a hematopoietic myeloproliferative disorder.The Chinese prescription Danggui Longhui Wan(DGLHW)has been utilized in CML treatment,but its underlying mechanisms remain unclear.In this study,we gathered 794 constituents,1249 drug targets,1654 disease genes and 129 intersection genes.GO and KEGG were used to analyze the function of these genes.Compatibility of prescription study showed that monarch drug,minister drug,assistant and guide drug played a synergistic role in the treatment of CML.In addition,we obtained 20 hub genes and 12 key components.Molecular docking indicated that the main compounds and core proteins had good binding ability.The results of this study also showed that DGLHW might play a role in the treatment of CML by affecting MAPK,PI3K/AKT,FoxO and p53 signaling pathways.

Observation on the Clinical Effect of Applying Venetoclax Combined with Demethylation Drug Therapy in Patients with Acute Myeloid Leukemia

Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P > 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.

Chidamide,Decitabine,Cytarabine,Aclarubicin,and Granulocyte Colony-stimulating Factor Therapy for Patients with Relapsed/Refractory Acute Myeloid Leukemia:A Retrospective Study from a Single-Center

Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.

Unusual presentation of extramedullary blast crisis in chronic myeloid leukemia:A case report

BACKGROUND Extramedullary blast crisis in chronic myeloid leukemia(CML)is an uncommon occurrence of leukemic blast infiltration in regions other than the bone marrow.Malignant infiltration of the serosal membranes should be considered in cases where CML presents with ascites or pleural effusion.CASE SUMMARY A 23-year-old female with CML presented with progressively worsening ascites and pleural effusion despite first-line tyrosine kinase inhibitor treatment.Her blood work indicated leukocytosis with myelocyte bulge and 2%blasts.Analysis of the patient’s bone marrow confirmed the chronic phase of CML.Abdominal ultrasound revealed hepatosplenomegaly with ascites.The fluid investigation of both ascites and pleural effusion revealed a predominance of neutrophils with exudate.However,no acid-fast bacilli or growth was observed after culturing.Although hydroxyurea reduced cell counts,there was no observed effect on ascites or pleural effusion.Repeat investigation of the ascitic and pleural fluid revealed a polymorphous myeloid cell population consisting of myelocytes,metamyelocytes,band forms,neutrophils and a few myeloblasts.Extramedullary blast crisis was suspected,and mutation analysis was performed.We switched the patient to dasatinib.The patient’s symptoms were relieved,and ascites and pleural effusion diminished.CONCLUSION Serosal membrane involvement in CML is extremely rare.In this case,the patient responded well to dasatinib treatment.

A novel t(3;12)(q21;p13) translocation in a patient with accelerated chronic myeloid leukemia after imatinib and nilotinib therapy

The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.

Monitoring and Analysis of Chinese Chronic Myeloid Leukemia Patients Who Have Stopped Tyrosine Kinase Inhibitor Therapy

Discontinuation of tyrosine kinase inhibitor(TKI)therapy after achieving a persistent deep molecular response(DMR)is an urgently needed treatment goal for chronic myeloid leukemia(CML)patients and has been included in the National Comprehensive Cancer Network(NCCN)guidelines(version 2.2017)for CML.Indeed,various studies have confirmed the feasibility of discontinuing TKI therapy.In this study,we analyzed data from 45 CML patients who had discontinued TKI therapy.Univariate analysis was performed to predict factors that were potentially related to treatment-free remission(TFR)and identify the differences between early relapse and late relapse.Out of the 45 patients,20 exhibited molecular relapse after a median follow-up of 18 months(range,1-54 months),and the estimated TFR at 24 months was 40%.The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes.Our results indicate that TKI discontinuation could be successfully put into practice in China.

The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

For patients with chronic myeloid leukemia（CML） failing imatinib therapy,second-generation tyrosine kinase inhibitors（TKIs） are recommended.Here,we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib,but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullar/ toxicity.Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs:A literature review

Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia:Two case reports

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.

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

Efficacy and Safety of Generic Dasatinib as a Second-line Treatment for Patients with Chronic Myeloid Leukemia:a Multicenter Retrospective Study in Hubei Province,China

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI)and it could be used as a second-line treatment for patients with chronic myeloid leukemia (CML).Yinishu,a generic dasatinib made in China,was approved by the China Food and Drug Administration in 2013 and it costs much less than the patented dasatinib SPRYCEL.The present study aimed to examine the efficacy and safety of Yinishu as a second-line treatment for CML by comparing the baseline clinical characteristics,rates of adverse events and efficacy between Yinishu and SPRYCEL groups. The results showed that there were no significant differences in the rates of optimal response between Yinishu and SPRYCEL for patients who started second-line treatment because of treatment failure.For patients who started second-line treatment because of intolerance of first-line treatment, their levels of BCR-ABL1/ABL1 on the international scale (BCR-ABL^IS)was maintained very low throughout the course of Yinishu treatment.Drug-related adverse events occurred with the same frequency in these two groups.It was confirmed that Yinishu was effective and safe as a second- line treatment for CML patients.Yinishu may be more suitable for patients who are economically unable to pay for the patented dasatinib SPRYCEL.

Gene mutations in a patient with chronic myelomonocytic leukemia and changes upon progression to acute myeloid leukemia and during treatment

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.

Coexistence of breakpoint cluster region-Abelson1 rearrangement and Janus kinase 2 V617F mutation in chronic myeloid leukemia: A case report

BACKGROUND The Janus kinase 2(JAK2) V617 F mutation is common in patients with breakpoint cluster region-Abelson1(BCR-ABL1)-negative myeloproliferative neoplasms,including polycythemia vera, essential thrombocythemia and primary myelofibrosis, but is rarely detected in BCR-ABL1-positive chronic myeloid leukemia(CML) patients. Here, we report a CML patient with both a BCR-ABL1 rearrangement and JAK2 V617 F mutation.CASE SUMMARY A 45-year-old Chinese woman was admitted to our department with a history of significant thrombocytosis for 20 d. Color Doppler ultrasound examination showed mild splenomegaly. Bone marrow aspiration revealed a karyotype of 46,XX, t(9;22)(q34;q11.2) in 20/20 metaphases by cytogenetic analysis,rearrangement of BCR-ABL1(32.31%) by fluorescent polymerase chain reaction(PCR) and mutation of JAK2 V617 F(10%) by PCR and Sanger DNA sequencing.The patient was diagnosed with CML and JAK2 V617 F mutation. Following treatment with imatinib for 3 mo, the patient had an optimal response and BCRABL1(IS) was 0.143%, while the mutation rate of JAK2 V617 F rose to 15%.CONCLUSION Emphasis should be placed on the detection of JAK2 mutation when CML is diagnosed to distinguish JAK2 mutation-positive CML and formulate treatment strategies.

Combination of Rapamycin and Imatinib in Treating Refractory Chronic Myeloid Leukemia Myeloid Blast Crisis:a Case Report

HRONIC myeloid leukemia （CML） is characterized by the presence of the BCR/ABL fusion gene, which is the result of a reciprocal translo cation between chromosomes 9 and 22, calledPhiladelphia （Ph） chromosome. Imatinib mesylate （imatinib）, a specific small molecular inhibitor of BCR/ABL, could improve the prognosis of CML and is now the standard drug applied in all phases of this disease} Despite the efficacy of imatinib, the development of resistance and the persistence of minimal residual disease have seriously impaired the efficiency of this medicine. Resistance may develop through several different mechanisms, such as mutations in the Abl kinase domain, BCR/ABL overexpression, or compensatory phosphatidylinositol 3 kinase （PI3K）/Akt/ mammalian target of rapamycin （mTOR） activation.2,3 Rapamycin, with mTOR as a potential therapeutic target, has been studied in patients with hematologic malignancies. Here we report a case of refractory CML myeloid blast crisissuccessfully treated by the combination of rapamycin and imatinib.

Anti-proliferative effects of a small molecule inhibitor of CDKAT7519 on chronic myeloid leukemia (CML) cells through haltingthe transition of cells from G2/M phase of the cell cycle

Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored.Given the involvement of cyclin-dependent kinases(CDKs)in the pathogenesis of CML,the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells.Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27.The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity,suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor,at least partly,through a c-Mycdependent mechanism.To the best of our knowledge,to date,no study has addressed the effect of autophagy on CML cell response to AT7519,and,herein,we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562.Overall,we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.

Phosphomonoester Phosphoethanolamine Induces Apoptosis in Human Chronic Myeloid Leukemia Cells

Background:Leukemia is a type of cancer that starts in the blood or blood-forming tissues.It results from the clonal proliferation of hematopoietic cells in the bone marrow and/or lymphoid tissues,which subsequently reach the peripheral circulation and can infiltrate other systems.There are many different kinds of leukemia,and treatments are different for each one.Chronic leukemia is with a slower growing than acute leukemia but could be just as life-threatening.Phospholipids are antitumor analogs,such as synthetic phosphoethanolamine,which is a phosphorylated compound capable of controlling cellular proliferation and inducing apoptosis in several types of tumor cells.Methods:K562 and K562-Lucena(MDR+)human chronic myeloid leukemia cells were treated with synthetic phosphoethanolamine(Pho-s).The viability was evaluated by sulforhodamine B(SRB)assay and cell cycle phases,apoptosis,markers expression,and mitochondrial potential were assessed by flow cytometry.Results:Tumor cells formed clusters in suspension and decreased significantly viability.The concentrations for IC50%were obtained.Pho-s treated were 43.1 mM(K562)and 145.9 mM(K562-Lucena MDR+)in a period of 24 hours.Pho-s induced changes in the distribution of cell population phases of cell cycle which showed an increase in fragmented DNA and increased markers expression envolved apoptosis pathways a decrease in the G1/G0 phase.Discussion:Treatment of K562 and K562-Lucena(MDR+)chronic myeloid leukemia cells with Pho-s showed dose and time dependent cytotoxic effects.This cytotoxicity induced a decrease in proliferative capacity,mitochondrial electrical potential,and consequently release of cytochrome C;inhibition of Bcl-2 family protein expression,increase in pro-apoptotic family members Bad and Bax,dependent on p53 expression.Conclusion:This study presented a significant therapeutic potential of Phos-s in this type of leukemia through the apoptotic effects on tumor cells independently of the molecular resistance profile(MDR+).

Therapy-Related Acute Myeloid Leukemia in A Primary Pulmonary Leiomyosarcoma Patient with Skin Metastasis

Primary pulmonary leiomyosarcoma （LMS） is a very unusual tumor.Although LMS has well-known metastatic potential,cutaneous metastasis is a remarkably uncommon.Exposure to cytotoxic agents could lead to ＂therapy-related myeloid neoplasm＂ （t-MN）.Starting from 2008,the World Health Organization （WHO） has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia （t-AML）,therapy-related myelodysplastic syndrome （t-MDS） and therapy-related myelodysplastic/myelo-proliferative neoplasm （t-MDS/MPN）.We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis.This patient achieved complete remission （CR） after three courses of IA regimen chemotherapy （idarubicin 5 mg/d,d 1-3;cytarabine 100 mg/d,d 1-5） and 1 course of HA chemotherapy regimen （homoharringtonine 3 mg/d,d 1-3;cytarabine 100 mg/d,d 1-7）.This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.

Time-series Analysis in Imatinib-resistant Chronic Myeloid Leukemia K562-cells under Different Drug Treatments

Chronic myeloid leukemia（CML） is characterized by the accumulation of active BCR-ABL protein. Imatinib is the first-line treatment of CML; however, many patients are resistant to this drug. In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in imatinib-resistant CML cells under different drug treatments. GSE24946 was downloaded from the GEO database, which included 17 samples of K562-r cells with（n=12） or without drug administration（n=5）. Three drug treatment groups were considered for this study： arsenic trioxide（ATO）, AMN107, and ATO＋AMN107. Each group had one sample at each time point（3, 12, 24, and 48 h）. Time-series genes with a ratio of standard deviation/average（coefficient of variation） 〉0.15 were screened, and their expression patterns were revealed based on Short Time-series Expression Miner（STEM）. Then, the functional enrichment analysis of time-series genes in each group was performed using DAVID, and the genes enriched in the top ten functional categories were extracted to detect their expression patterns. Different time-series genes were identified in the three groups, and most of them were enriched in the ribosome and oxidative phosphorylation pathways. Time-series genes in the three treatment groups had different expression patterns and functions. Time-series genes in the ATO group（e.g. CCNA2 and DAB2） were significantly associated with cell adhesion, those in the AMN107 group were related to cellular carbohydrate metabolic process, while those in the ATO＋AMN107 group（e.g. AP2M1） were significantly related to cell proliferation and antigen processing. In imatinib-resistant CML cells, ATO could influence genes related to cell adhesion, AMN107 might affect genes involved in cellular carbohydrate metabolism, and the combination therapy might regulate genes involved in cell proliferation.

The m^(6)A regulator KIAA1429 stabilizes RAB27B mRNA and promotes the progression of chronic myeloid leukemia and resistance to targeted therapy

Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological processes.KIAA1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is unclear.In this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML.Notably,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib resistance.Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to imatinib.Moreover,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis.Rucaparib,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis.Rucaparib also inhibited the tumorigenesis of CML cells in vivo.The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib.Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML progression.Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.

Targeting leukemia stem cells:The new goal of therapy in adult acute myeloid leukemia

The most popular view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems.Leukemia contains a subpopulation of cells that display characteristics of stem cells.These cells maintain tumor growth.The properties of leukemia stem cells indicate that current conventional chemotherapy, directed against the bulk of the tumor,will not be effective.Leukemia stem cells are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and thus contribute to treatment failure. New strategies are required that specifically target this malignant stem cell population.