Qitian Mu

High expression of Musashi-2 indicates poor prognosis in adult B-cell acute lymphoblastic leukemia

Musashi-2 (MSI2) expression of 116 adult B-cells acute lymphoblastic leukemia (B-ALL) patients was measured by real-time PCR. Kaplan-Meier analysis showed that patients with high MSI2 expression had inferior overall survival (OS) (P=0.004), event free survival (EFS) (P=0.001) and relapse free survival (RFS) (P=0.018) in BCR-ABL-negative B-ALL. Multivariate models revealed that, besides WBC more than 30×10(9)/L and IK6 variant of IKZF1, high MSI2 expression was also an independent prognostic factor for adult BCR-ABL-negative B-ALL. Our data suggest that high MSI2 expression could indicate poor prognosis and facilitate risk and treatment stratification in adult BCR-ABL-negative B-ALL.

High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia

The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1/2 expression in 320 patients with cytogenetically normal AML (CN‐AML) by quantitative real‐time reverse‐transcription polymerase chain reaction. High expression of IDH1 was predominant in patients with FLT3‐ITD and DNMT3A mutations and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of microRNA 181 family. Prognosis was adversely affected by high IDH1 expression, with shorter overall survival and event‐free survival in the context of clinical characteristics, including age, WBC count, and gene mutations of NPM1, FLT3‐ITD, CEBPA, IDH1, IDH2 and DNMT3A in CN‐AML. Moreover, the clinical outcome of IDH1 expression in terms of overall survival, event‐free survival and complete remission rate still remained in multivariate models in CN‐AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG‐1999 protocol. Our results demonstrated that high IDH1 expression is associated with a poor prognosis of CN‐AML.

Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT.

10058-F4, a c-Myc inhibitor, markedly increases valproic acid-induced cell death in Jurkat and CCRF-CEM T-lymphoblastic leukemia cells

Adult T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis. Although it has been found that activation of Notch1 signaling occurs in >50% T-ALL patients, γ-secretase inhibitors that target Notch1 signaling are of limited efficacy. However, c-Myc is an important direct target of Notch1 and, thus, c-Myc is another potential therapeutic target for T-ALL. Valproic acid (VPA), a histone deacetylase inhibitor, has been reported to treat various hematological malignancies. In the present study, we showed that c-Myc expression, at a transcriptional level, was dose-dependently downregulated in VPA-induced growth inhibition in T-ALL cell lines, Jurkat and CCRF-CEM cells. 10058-F4, a small molecule c-Myc inhibitor, could increase the downregulation of c-Myc and markedly increase the growth inhibition and cell death induced by VPA in Jurkat and CCRF-CEM cells, which was accompanied by obvious cleavage of capase-3. Z-VAD-FMK, a caspase inhibitor, partially prevented the anti-leukemic effect. The results of the present study suggest that c-Myc inhibitors increase cell death induced by VPA in a caspase-dependent and -independent manner, and their combination could be a potent therapeutic strategy for adult T-ALL patients.

Outcome prediction by the transcript level of BCR-ABL at 3 months in patients with chronic myeloid leukemia treated with imatinib--a single institution historical experience.

The BCR-ABL transcript level (≤ 10%) at 3 months after tyrosine kinase inhibitors can predict long term outcome in the patients with chronic myeloid leukemia in chronic phase (CML-CP). However, the significance of transcript level was still not determined in different risk groups of patients. A total of 299 patients with CML-CP were enrolled and stratified according to prior interferon-α (IFN) treatment, age, and interval time between diagnosis and imatinib treatment to investigate the prediction value of BCR-ABL transcript level for overall survival (OS), event-free survival (EFS), progression-free survival (PFS). Univariate and multivariate analysis proved that BCR-ABL transcript level at 3 months were associated with the treatment outcome. However, in the patients with prior IFN treatment, younger age, and longer interval between diagnosis and IM treatment, the predictive value of transcript value remain obscure in terms of EFS, PFS and OS, respectively, as well as cumulative incidence of PCyR, CCR, MMR and CMR. In conclusion, the transcript level of BCR-ABL at 3 months could serve as a predictive parameter, but should be used with caution.

Acquired Robertsonian translocation is not always suggestive of poor prognosis: a case of acquired Rob(13;14) in Philadelphia chromosome-negative cells of chronic myelogenous leukemia

Robertsonian translocations are the most common constitutional chromosomal changes in the general population, at about one per 1000, while only approximately 3% of these abnormalities are acquired [1]. Acquired Robertsonian translocations occur also at low frequency in hematological malignancies. There have been scattered reports about these rearrangements, in which most authors believed their cases were rare, but Welborn’s systematic study [2] indicated that acquired Robertsonian translocations are more common in hematological malignancies than originally thought, approximately one per 325 cases. Der(13;14)(q10;q10), the most common rearrangement among the Robertsonian translocations, accounted for 74% of all cases, and only 6% of acquired ones, which were mainly observed in acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL). Among myeloid neoplasms there were only three cases with acquired Rob(13;14) reported—two in acute myelogenous leukemia (AML) [3,4] and one in myelodysplastic syndromes (MDS) [5]—all of which were accompanied by other chromosome abnormalities, according to a literature review. Patients with hematological malignancies of acquired Robertsonian translocation have a very poor prognosis [2]. However, we describe a case showing that acquired Rob(13;14) in chronic myelogenous leukemia (CML) during imatinib treatment was not associated with a poor prognosis. In May 2002, a 56-year-old male patient was admitted to our hospital with fatigue, weight loss, and upper abdominal malaise. Massive splenomegaly was detected by physical examination. The blood count revealed white blood cells (WBC) 84.86 10/L, platelets (PLT) 8786 10/L, hemoglobin (Hb) 129 g/L, and hematocrit (Hct) 38.2%. Bone marrow smears showed increased cellularity with a maturation pattern of 2% blasts, 1% promyelocytes, 18.5% myelocytes, 27.5% metamyelocytes, 22.5% band cells, 13.5% segmented, 3% eosinophils, and 1.5% basophils. The myeloid:erythroid (M:E) ratio was 11.9. Cytogenetic analysis showed that the reciprocal t(9;22)(q34;q11) was found in all 10 metaphases. The patient was diagnosed with CML in chronic phase. Interferon-a usage (36 10 U, 3 days per week) resulted in a major hematological response (MHR), but no cytogenetic response was achieved after 3 months. Cytogenetic analysis still showed 100% t(9;22), without additional chromosome abnormalities. In August 2004, while still in CML chronic phase, the patient started treatment with imatinib 400 mg per day, resulting in a major cytogenetic response (MCR) after 10 months. Although complete cytogenetic response (CCR) was achieved in June 2006, Rob(13;14) was found in Philadelphia chromosome (Ph)-negative cells in five of 20 metaphases

Overexpression of musashi2 is possibly associated with chemoresistance in T-cell acute lymphoblastic leukemia

Musashi2 (MSI2), an evolutionarily conserved RNA-binding protein, plays a critical and compensatory role in hematopoietic stem cells [1,2]. Recently, a study demonstrated MSI2 expression level incr...