Zap-70 positive chronic lymphocytic leukemia co-existing with Jak 2 V671F positive essential thrombocythemia: A common defective stem cell?

Essential thrombocythemia (ET) co-existing with chronic lymphocytic leukemia (CLL) is extremely rare. We report two cases of ET with Jak 2 V617F in Zap-70+ CLL. ET is a myeloproliferative stem cell disease. Zap-70 expression in CLL correlates with non-mutated immunoglobulin genes. The occurrence of a less mature CLL in patients with a pluripotential stem cell disease raises the possibility that an initial "trigger hit" occurred in a pre-Jak 2 common early progenitor in these patients. Subsequent additional molecular events accumulated independently following myeloid and lymphoid differentiation, leading to the development of two diseases of likely identical origin but different lineages.     

NCCN非小细胞肺癌临床实践指南(2023V1、V2版)更新要点解读

2023年第1版及第2版NCCN非小细胞肺癌(NSCLC)临床实践指南相较2022年第6版版本做出了部分更新,主要将术前活检应用范围扩大并强调了术前新辅助免疫治疗的评估与应用,同时术后靶向/免疫辅助治疗的适用范围扩大,且将帕博丽珠单抗纳入治疗选择,靶向治疗方面主要对EGFR 20号外显子插入突变、KRAS G12C突变、ROS1重排患者的治疗做出更新。该文将对本次指南中关于术前活检及新辅助治疗、术后辅助治疗及晚期肺癌的靶向治疗等方面更新进行阐述及解读。     

Reversing the multidrug resistance in acute leukemia: Until the leukemia initiating cell?

Reversal of drug resistance is of pivotal importance in order to improve the results of chemotherapy. Monitoring of such reversal is necessary in order to analyze the results of clinical trials. Nonetheless, the leukemia cell population to eradicate is the leukemia initiating cells characterized by a CD34+CD38- phenotype. The evaluation of novel drug resistance modulators should be performed both in the whole leukemic cell population and in the leukemia initiating cell compartment, that is responsible for "mature" leukemia cells replenishment.     

Human T cell leukemia virus type 1 (HTLV-1) and oncogene or oncomiR addiction?

The mechanism of HTLV-1 transformation of cells to Adult T cell leukemia (ATL) remains not fully understood. Currently, the viral Tax oncoprotein is known to be required to initiate transformation. Emerging evidence suggests that Tax is not needed to maintain the transformed ATL phenotype. Recent studies have shown that HTLV-1 transformed cells show deregulated expression of cellular microRNAs (miRNAs). Here we discuss the possibility that early ATL cells are Tax-oncogene-addicted while late ATL cells are oncogenic microRNA (oncomiR) - addicted. The potential utility of interrupting oncomiR addiction as a cancer treatment is broached.     

A MENage à Trois in leukemia

Menin binds to the N terminus of the chromatin-remodeling histone methyltransferase MLL and is essential for the transforming activity of at least several oncogenic MLL fusion proteins. In this issue, Yokoyama and Cleary (2008) show that menin's essential, and perhaps only, contribution to leukemia is to tether a third protein, LEDGF--a chromatin-associated protein implicated in leukemia and several other disease states--to MLL. Thus, this study identifies a new, critical player in leukemias caused by MLL fusion proteins and defines the biochemical function of menin in the MLL complex.     

Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia

B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.     

Prognostic impact of δ-like ligand 4 and Notch1 in acute myeloid leukemia

Notch signaling plays a critical role in embryonic vascular development and tumor angiogenesis. The present study was conducted to investigate the prognostic role of the angiogenesis-related Notch ligand and the receptor in acute myeloid leukemia (AML) and assess whether their expression correlates with that of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2. Bone marrow mononuclear cells from 60 untreated AML patients and 40 healthy controls were obtained. Real-time RT-PCR was performed to evaluate the mRNA expression of δ-like ligand 4 (Dll4), Notch1, VEGF, VEGF receptor (VEGFR)-1, VEGFR-2, Ang-1, Ang-2 and Tie2. Western blot analysis was used to determine the protein levels of Dll4 and Notch1. The results demonstrated that Dll4, Notch1, VEGF, VEGFR-2 and Ang-2 expression were significantly higher in untreated AML patients than in the controls. Univariate analysis of factors associated with the overall survival showed a significantly shorter survival in patients with the unfavorable karyotype, higher Dll4 expression, higher Notch1 expression, higher VEGF expression or higher Ang-2 expression. Furthermore, multivariate analysis revealed that the karyotype and expression levels of Notch1, Dll4, VEGF and Ang-2 were independent prognostic factors for overall survival. Additionally, the prognostic value of Dll4 expression (but not Notch1) was more significant in the subgroup consisting of patients with intermediate-risk cytogenetics. Subgroup analysis showed that Notch1 and Dll4 expression levels had a prognostic impact on patients with high VEGF or Ang-2 levels. Taken together, our data provide evidence that the activation of the Notch pathway may indicate an unfavorable prognosis in AML. In particular, Dll4 may be a relevant prognostic marker in intermediate-risk AML.     

Rap1GAP alters leukemia cell differentiation, apoptosis and invasion in vitro

Rap1GAP which regulates the GTP-GDP form switch of Rap1 is a member of the GTPase-activating protein (GAP) family and has recently received substantial attention. Rap1GAP is thought of as a putative tumor suppressor gene and plays an important role in human tumor progression including pancreatic cancer, thyroid cancer and melanoma. In the current study, we found that the expression of Rap1GAP was lower in acute myeloid leukemia (AML) patients compared to non-malignant blood disease patients. The expression of Rap1GAP was also low in HL-60, NB4, U937 and SHI-1 myeloid leukemia cell lines. Upregulated Rap1GAP in NB4 and HL-60 cells promoted cell differentiation induced by ATRA or TPA compared to the empty vector control cells. Furthermore, Rap1GAP-transfected cells also showed a higher rate of apoptosis in response to arsenic trioxide compared to the control counterpart cells. In addition, we found that increased expression of Rap1GAP promoted leukemia cell invasion may be due to matrix metalloproteinase 9 (MMP9). In conclusion, these results demonstrated that Rap1GAP promoted leukemia cell differentiation and apoptosis, but increased leukemia cell invasion in?vitro.     

Can inhibition of the SDF-1/CXCR4 axis eradicate acute leukemia?

Poor prognosis of acute leukemia with current treatments is mainly due to the relapse of the disease following chemotherapy. In the last decade, an emerging concept has proposed that the leukemia stem cells (LSCs) and their interactions with the BM microenvironment are the major cause of the acute leukemia relapse. Adhesion to the stromal niche is crucial for LSCs as it directly supports self-renewal, proliferation, arrest of differentiation and protects from damaging chemo-agents. One of the key players in this crosstalk between leukemic cells and the BM stroma niche is the chemokine SDF-1. SDF-1 regulates the process of homing and engraftment of LSCs into the BM and inhibition of its receptor CXCR4 induces leukemic cell mobilization into the circulation. However, besides its chemotactic and adhesive functions, SDF-1 is also a pleiotropic cytokine that regulates leukemic cell proliferation as well as their program of differentiation. CXCR4 antagonists are used in combination with chemotherapy in preclinical and clinical studies, which demonstrate that blocking CXCR4 is a novel promising approach of therapy. In this review, we focus on the multifaceted SDF-1/CXCR4 axis in acute leukemia and discuss how targeting this pathway could provide potential interest to eradicate the LSCs.     

Parental smoking, CYP1A1 genetic polymorphisms and childhood leukemia (Québec, Canada)

Objective: To evaluate the effect of parental smoking on childhood acute lymphoblastic leukemia and to determine if it is modified by child genetic polymorphisms. Methods: We carried out a case–control study in Québec, Canada, including 491 incident cases aged 0–9 years and as many healthy controls matched on age and sex. Each parent was interviewed separately with respect to smoking habits during and after pregnancy. In addition, we carried out a case-only substudy with 158 cases classified according to presence or absence of the alleles *2A, *2B, and *4 in the CYP1A1 gene. Results: There were small risk increases with maternal smoking during the later trimesters. Interaction odds ratios were increased (although often not significantly) for the CYP1A1*4 allele at high levels of maternal smoking in the last trimesters and at low level of paternal postnatal smoking, and decreased for the CYP1A1*2B allele. The latter appeared to confer a protective advantage at low levels for maternal prenatal smoking and at high levels for paternal postnatal smoking. Conclusions: Reported smoking habits showed no association with leukemia; risks for genetic polymorphisms lacked precision but indicated that the effect of parental smoking could be modified by variant alleles in the CYP1A1 gene.     

干扰素对JAK2 V617F阳性骨髓增殖性肿瘤PD-1/PD-L1及Treg表达的影响

 目的 探讨干扰素-alpha-2b（IFN-α2b）对JAK2 V617F阳性骨髓增殖性肿瘤（MPN）患者中程序性死亡受体-1（PD-1）、程序性死亡配体-1 （PD-L1）及CD4+ CD25+ Foxp3+调节性T细胞（Treg）表达的影响及临床意义。方法 收集JAK2 V617F阳性MPN患者61例，包括初治组41例、IFN-α2b治疗组20例，健康对照组20例。应用荧光定量PCR检测JAK2 V617F/JAK2突变率，流式细胞术检测PD-1、PD-L1、Treg的表达情况。选取15例患者骨髓及外周血标本进行体外细胞培养，应用1×106 U/L IFN-α2b作用48 h后检测PD-1、PD-L1及Treg表达情况。结果 初治组的JAK2 V617F、PD-1、PD-L1及Treg表达明显高于IFN-α2b治疗组及对照组（均P<0.05）。JAK2 V617F突变量≥50%患者骨髓髓系细胞PD-1、PD-L1及外周血Treg细胞均明显高于突变量<50%患者（均P<0.05）。相关性分析结果显示JAK2 V617F突变量与骨髓髓系细胞PD-1、PD-L1和淋巴细胞PD-1呈正相关，与Treg表达无相关性。1×106 U/L IFN-α2b作用48 h后能够体外抑制MPN原代细胞PD-1、PD-L1及Treg的表达（P<0.05）。结论 PD-1、PD-L1及Treg共同参与了MPN的发病过程，干扰素能够不同程度抑制MPNJAK2 V617F、PD-1、PD-L1及Treg表达，进而抑制MPN的进展。     

伴有JAK2 V617F突变的慢性中性粒细胞白血病1例并文献复习

目的：探讨伴有JAK2基因V617F突变的慢性中性粒细胞白血病（CNL）的实验室特征。方法：通过骨髓涂片进行细胞形态学分析诊断;采用实时荧光定量PCR方法检测BCR-ABL融合基因;实时荧光定量PCR方法及DNA测序方法检测JAK2 V617F突变;RHG显带进行常规染色体核型分析。结果：细胞形态学诊断为慢性中性粒细胞白血病;BCR/ABL融合基因为阴性;存在JAK2 V617F杂合突变;染色体分析结果为正常核型。结论：JAK2 V617F突变在慢性中性粒细胞白血病中很少见,具有该突变的CNL患者有较长的生存期,JAK2 V617F突变可能提示预后良好。     

伴有JAK2 V617F突变的慢性中性粒细胞白血病1例并文献复习

目的:探讨伴有JAK2基因V617F突变的慢性中性粒细胞白血病(CNL)的实验室特征。方法:通过骨髓涂片进行细胞形态学分析诊断;采用实时荧光定量PCR方法检测BCR-ABL融合基因;实时荧光定量PCR方法及DNA测序方法检测JAK2 V617F突变;RHG显带进行常规染色体核型分析。结果:细胞形态学诊断为慢性中性粒细胞白血病;BCR/ABL融合基因为阴性;存在JAK2 V617F杂合突变;染色体分析结果为正常核型。结论:JAK2 V617F突变在慢性中性粒细胞白血病中很少见,具有该突变的CNL患者有较长的生存期,JAK2 V617F突变可能提示预后良好。