Decitabine-based treatment strategy improved the outcome of HSCT in JMML: a retrospective cohort study.

Introduction: Pre-HSCT disease control, suboptimal long-term prognosis, and a high recurrence incidence (RI) continue to pose significant challenges for hematopoietic stem cell transplantation (HSCT) in juvenile myelomonocytic leukemia (JMML) patients. Methods: This retrospective cohort study assessed the effectiveness of a decitabine (DAC)-based protocol in JMML patients undergoing HSCT. The pre-HSCT treatment includes initial and bridging treatment. The efficacy of DAC monotherapy versus DAC combined with cytotoxic chemotherapy(C-DAC) as initial treatment was compared, followed by DAC plus FLAG (fludarabine, cytarabine, and GCSF) as bridging treatment. The HSCT regimens were based on DAC, fludarabine, and busulfan. Post-HSCT, low-dose DAC was used as maintenance therapy. The study endpoints focused on pretransplantation simplified clinical response and post-HSCT survival. Results: There were 109 patients, including 45 receiving DAC monotherapy and 64 undergoing C-DAC treatment. 106 patients completed bridging treatment. All patients were administered planned HSCT regimens and post-HSCT treatment. The initial treatment resulted in 88.1% of patients achieving clinical remission without a significant difference between the DAC and C-DAC groups (p=0.769). Clinical remission rates significantly improved following bridging treatment (p=0.019). The 5-year overall survival, leukemia-free survival, and RI were 92.2%, 88.4%, and 8.0%, respectively. A poor clinical response to pre-HSCT treatment emerged as a risk factor for OS (hazard ratio: 9.8, 95% CI: 2.3-41.1, p=0.002). Conclusion: Implementing a DAC-based administration strategy throughout the pre-HSCT period, during HSCT regimens, and in post-HSCT maintenance significantly reduced relapse and improved survival in JMML patients. Both DAC monotherapy and the DAC plus FLAG protocol proved effective as pre-HSCT treatments.

[The Effect of hnRNPK/Beclin1 Signaling on the Drug Resistance of Imatinib in Ph+ Leukemia].

OBJECTIVE: To explore the effect of hnRNPK/Beclin1 signaling on the drug resistance of imatinib in Ph+ leukemia. METHODS: Expression level of hnRNPK was verified in the imatinib resistant and sensitive Ph+ leukemia cell lines by using Western blot. hnRNPK expression was down-regulated by using RNAi. Expression level of LC3I/II and Beclin1 were detected by Western blot and the sensitivity of imatinib was analyzed by CCK-8 assay before and after modulation of hnRNPK expression. RESULTS: hnRNPK showed overexpressed in imatinib resistant leukemia cell line. After the expression level of hnRNPK was down-regulated by RNAi, the sensitivity of drug resistance lines to imatinib restored, while the expression level of LC3I/II and Beclin1 were consistant with the modulation of hnRNPK expression. CONCLUSION: hnRNP K/Beclin1 signaling may be involved in the development of imatinib resistance in Ph+ leukemia through the regulation of autophagy.

Langerhans cell histiocytosis developing acute lymphoblastic leukemia.

The sequential occurrence of Langerhans cell histiocytosis and acute leukemia in only one individual has been reported previously; however, it is rarely observed that Langerhans cell histiocytosis can transform into acute lymphoblastic leukemia, and the underlying mechanisms remain unclear. In this report, we have analyzed a case of acute lymphoblastic leukemia converted from Langerhans cell histiocytosis using high-throughput sequencing method, and found that mitogen-activated protein kinase gene mutation, which can act as a marker for poor prognosis, might be involved in disease transformation. This is the first description about acute lymphoblastic leukemia B-cell type after Langerhans cell histiocytosis diagnosis and therapy in China.

hnRNPK/Beclin1 signaling regulates autophagy to promote imatinib resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia cells.

This study sought to clarify the role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a regulator of imatinib resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Expression of hnRNPK was assessed in Ph+ ALL leukemia cells in vitro and in vivo, and imatinib susceptibility was assessed via CCK-8 assay. In cells in which hnRNPK levels had or had not been modulated, LC3Ⅰ/Ⅱ and mTOR/p-ERK/Beclin1 levels were assessed via Western blotting, while electron microscopy was used to evaluate autophagic vacuole formation. Interactions between hnRNPK and Beclin1 were assessed through an RNA binding protein immunoprecipitation assay. Imatinib-resistant Ph+ ALL cell lines and patient bone marrow samples exhibited significant hnRNPK overexpression. Knockdown of hnRNPK increased the imatinib sensitivity of these tumor cells and decreased in vivo tumor burden in a xenograft model system as evidenced by a reduction in tumor volume. Levels of LC3Ⅰ/Ⅱ and Beclin1, but not p-ERK and mTOR, were consistent with the regulatory activity of hnRNPK. Electron microscopy revealed that imatinib-resistant cells harbored significantly more autophagic vacuoles relative to wild-type cells, while hnRNPK knockdown reduced the number of these vacuoles. In an RNA-binding protein immunoprecipitation assay, anti-hnRNPK was able to precipitate the Beclin1 mRNA. These results suggest that the hnRNPK/Beclin1 signaling pathway may play a role in shaping imatinib resistance in Ph+ ALL cells.

[hnRNP K Contributes to Adriamycin Resistance in Acute Myeloid Leukemia through Regulating Autophagy].

OBJECTIVE: To explore the role of heterogeneous nuclear ribonucleoprotein(hnRNP) K regulating autophagy in the drug resistance of acute myeloid leukemia, so as to provide a new molecular marker for treatment of leukemia. METHODS: The relationship between the expression level of hnRNP K and the drug resistance of myeloid leukemia was verified by fluorescence quantitative PCR; the expression of autophagy related protein LC3I/ II was detected by Western blot after the hnRNP K was modulated by RNA interference technology; the sensitivity of leukemia cells to doxorubicin was analyzed before and after the expression of hnRNP K were modulatd. RESULTS: The expression of hnRNP K and LC3I/II significantly increased in bone marrow nonremission patients and in drug resistant cell line, however, the expression of LC3I/ II decreased when the expression of hnRNP K were reduced, while the sensitivity of cells to adriamycin could be recovered. CONCLUSION: hnRNP K may be involved in the formation of adriamycin resistance in acute myeloid leukemia by regulating autophagy.

HnRNP K contributes to drug resistance in acute myeloid leukemia through the regulation of autophagy.

The goal of this study was to explore the role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in drug resistance through the regulation of autophagy in acute myeloid leukemia (AML). First, we used fluorescence quantitative polymerase chain reaction (PCR) to verify the connection between the expression level of hnRNP K and the level of drug resistance in AML. We then used Western blotting to determine the expression level of the autophagy-related proteins microtubule-associated protein light chain 3 I and II (LC3 I/II) after the modulation of hnRNP K by ribonucleic acid (RNA) interference. Finally, an analysis of adriamycin drug sensitivity was conducted before and after the modulation of hnRNP K expression. hnRNP K and LC3 I/II were significantly overexpressed in the bone marrow of nonremission patients and in drug-resistant cell lines; however, the expression of LC3 I/II was decreased when the expression of hnRNP K was reduced and drug sensitivity to adriamycin could be restored. hnRNP K may be involved in the development of adriamycin resistance in AML through the regulation of autophagy.