Development of t(8;21) and RUNX1-RUNX1T1 in the Philadelphia-positive clone of a patient with chronic myelogenous leukemia: additional evidence for multiple steps involved in disease progression

A 65-year-old patient with a high hemoglobin and hematocrit was treated for 14 months with therapeutic phlebotomy when cytogenetics of bone marrow revealed 100% cells with the Ph chromosome and 45% of the Ph+ cells contained trisomy 8. Treatment with tyrosine kinase inhibitors did not reduce the BCR-ABL1 fusion positive clone. Instead, the Ph positive cells acquired further the t(8;21)/RUNX1-RUNX1T1, del(4q) and trisomy 15 chromosomal abnormalities which were resistant to further treatment. Literature review revealed eight other patients who either had t(9;22) and t(8;21) simultaneously or developed t(8;21) in the Ph positive clone. We conclude that there are rare patients with CML who either present in blast crisis with coexistence of t(9;22) and t(8;21) with or without +8, or progress to blast crisis with acquiring RUNX1-RUNX1T1 in the BCR-ABL1 clone which may or may not be therapy related and represent a later event in a multistep pathogenesis.     

血红素加氧酶-1对慢性粒细胞白血病细胞凋亡效应的研究

目的探讨HO-1在慢性粒细胞白血病（以下简称慢粒）中的表达,研究其对抗细胞凋亡的效应,并研究抑制HO-1的表达对细胞凋亡的影响。方法探讨HO-1在慢性粒细胞白血病中的表达,研究其对抗细胞凋亡的效应,并研究抑制HO-1的表达对细胞凋亡的影响。结果RT-PCR结果显示骨髓血中HO-1的表达呈组成性,与对照组相比,诱导K562细胞HO-1的表达促进了细胞的生长（P＆lt;0.05）,并且这种表达成剂量依赖性,而抑制HO-1的表达促进了细胞的凋亡（P＆lt;0.05）,细胞的存活率只有对照组的30%。结论慢粒标本中HO-1的表达呈组成性,HO-1是一种可诱导型分子,并发挥抗凋亡效应,抑制HO-1的表达可能成为治疗慢粒的新方法。     

慢性粒细胞白血病34例临床分析

目的 探讨慢性粒细胞白血病的临床表现与治疗.方法 对34例CML患者临床资料进行分析.结果 本组34例CML患者,3例放弃治疗,1例住院3d抢救无效死亡,6例初诊即为加速期.剩余24例慢性期患者于确诊后多以马利兰和(或)羟基脲为主治疗,16例患者同时加用干扰素治疗.极个别患者采用HA联合化疗或甲异靛治疗(各1例).有5例于病程中发生急变,急变发生率为20.8%.其中急粒变3例,急淋变2例,这些患者由确诊慢粒到急变的时间为2～67个月,平均为18.7个月.6例进入加速期的患者各采用NA、HA、从等方案,有5例治疗有效.转为慢性期,但平均2个月复发.很快急变.5例急变患者亦各给予HA、AA、EHA、COAP、VDLP等方案化疗,2例急淋变患者及1例急粒变患者获短期部分缓解.结论 CML急变期的病情比加速期更凶险,属难治性白血病的一种类型,治疗采用与急性白血病相同的联合化疗方案,疗效与原始细胞形态有关,急淋变效果优于急粒变.     

Comparative analysis of the impact of risk profile and of drug therapy on survival in CML using Sokal's index and a new score

Survival times in chronic myeloid leukaemia (CML) may vary widely depending on the risk profiles of patients. This fact is frequently not, or not sufficiently, considered in evaluating survival in CML, and some studies do not report risk profiles. Therefore we analysed the relative impact of risk profile and therapy on survival using the median survival times of therapy groups and of risk groups of the three-arm randomized German CML Study I (interferon alpha v hydroxyurea v busulphan; median survival times 65 v 56 v 45 months, n =490, median observation time 70.4 months). The impact of risk profile (Sokal) on survival as determined by the survival difference between high and low risk patients (40 months) was twice the maximum survival difference between treatment groups (20 months). A similar ratio was obtained after stratification for therapy and for risk profile. Since Sokal's index has been reported to prognostically discriminate IFN-treated patients less well than chemotherapy-treated patients, a new score with better discrimination of IFN-treated patients was also used. The results were similar for both scores. We conclude that the risk profile at diagnosis is still more important for survival of CML patients than therapy. Therefore patients should be stratified according to risk profile for comparisons of survival times between studies and treatment arms.     

The role of long non‐coding RNAs and downstream signaling pathways in leukemia progression

The study of long non‐coding RNAs (lncRNA) is a newly established field and our knowledge about them is rapidly growing. These kinds of RNAs are unchanged parts of the genome throughout evolution, that modulate cell growth, differentiation, and apoptosis during diverse physiological and pathological processes including leukemia development. They have the capability to be useful biomarkers for the diagnosis, clinical typing, prognosis, as well as potential therapeutic targets. In this study, we summarized the role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia.     

Lactate Maintains BCR/Abl Expression and Signaling in Chronic Myeloid Leukemia Cells Under Nutrient Restriction

This study was directed to deepen the effects of nutrient shortage on BCR/Ablprotein expression and signaling in chronic myeloid leukemia (CML) cells. The backbone of the study was cell culture in medium lacking glucose, the consumption of which we had previously shown to drive BCR/Ablprotein suppression, and glutamine, the other main nutrient besides glucose. In this context, we focused on the role of lactate, the main by-product of glucose metabolism under conditions of rapid cell growth, in particular as a modulator of the maintenance of CML stem/progenitor cell potential, a crucial determinant of disease course and relapse of disease. The results obtained indicated that lactate is a powerful surrogate of glucose to prevent the suppression of BCR/Abl signaling and is therefore capable to maintain BCR/Abl-dependent CML stem/progenitor cell potential. A number of metabolism-related functional and phenotypical features of CML cells were also determined. Among these, we focused on the effect of lactate on oxygen consumption rate, the dependence of this effect on the cell surface lactate carrier MCT-1, and the relationship of the lactate effect to pyruvate and to the activity of mitochondrial pyruvate carrier.     

Do we need more drugs for chronic myeloid leukemia?

The introduction of protein tyrosine kinase inhibitors (TKIs) in 1998 transformed the management of chronic myeloid leukemia (CML), leading to significantly reduced mortality and improved 5 year survival rates. However, the CML community is faced with several clinical issues that need to be addressed. Ten to 15% of CML patients are diagnosed in advanced phase, and small numbers of chronic phase (CP) cases experience disease progression each year during treatment. For these patients, TKIs induce only transient responses and alternative treatment strategies are urgently required. Depending on choice of first line TKI, approximately 30% of CML CP cases show suboptimal responses, due to a combination of poor compliance, drug intolerance, and drug resistance, with approximately 50% of TKI-resistance caused by kinase domain mutations and the remainder due to unknown mechanisms. Finally, the chance of successful treatment discontinuation is on the order of only 10–20% related to disease persistence. Disease persistence is a poorly understood phenomenon; all CML patients have functional Philadelphia positive (Ph+) stem and progenitor cells in their bone marrows and continue to express BCR-ABL1 by DNA PCR, even when in very deep remission and following treatment discontinuation. What controls the maintenance of these persisting cells, whether it is necessary to fully eradicate the malignant clone to achieve cure, and how that might be approached therapeutically are open questions.     

干扰素-α在治疗慢性粒细胞白血病患者中的综合应用价值

目的：分析干扰素-α对慢性粒细胞白血病（ CML）血清疾病相关细胞因子水平的影响,探讨其综合应用价值。方法60例CML患者作为观察组及30例正常健康人群作为正常对照组,60例CML患者又随机分为2组,对照组和干扰素治疗组各30例。比较不同人群间血清PGE-2、MMP-2、bFGF、ALP及IL-6等细胞因子水平差异。比较对照组和干扰素治疗组患者采用干扰素-α治疗前后血清上述细胞因子水平以及疗效差异。结果 CML血清PGE-2、MMP-2、bF-GF、ALP及IL-6水平显著高于正常对照组,P＜0．05。干扰素治疗组治疗6周后血清PGE-2、MMP-2、bFGF、ALP及IL-6水平显著低于对照组,疗效指标CHR、CCyR、CMR则显著优于对照组,P＜0．05。结论干扰素-α对肿瘤生长相关的细胞因子具有调节作用,能有效缓解CML患者临床症状,在CML治疗中具有积极的意义。