The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia.

The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.

Immature reticulocyte fraction is an early predictor of bone marrow recovery post chemotherapy in patients with acute leukemia.

OBJECTIVE: To establish the benefits of immature reticulocyte fraction (IRF) measurement using an automated hematology cells analyzer over absolute neutrophil count (ANC) in predicting bone marrow recovery post induction chemotherapy. METHODS: A prospective observational study was carried out in the Departments of Pathology, Medicine, and Pediatrics, Universiti Kebangsaan Malaysia, Medical Center (UKMMC), Kuala Lumpur, Malaysia during a period of 19 months from April 2009 to December 2010 to assess the bone marrow recovery in patients with acute leukemia. A total of 22 patients in remission induction phases were enrolled in this study. The blood specimens were collected from day zero after chemotherapy, and every 3 days until patients recovered hematologically. All blood samples were measured for ANC and IRF using an automated hematology analyzer (Beckman-Coulter LH750). RESULTS: The percentage of patients showing IRF recovery earlier than ANC recovery was 63.6% (14 out of 22 patients). There was a significant difference in the mean number of days for IRF recovery as compared with ANC recovery (14.05 and 17.18 days), p=0.005. CONCLUSION: This study proved that IRF was more useful in predicting bone marrow recovery in a patient with acute leukemia post induction chemotherapy compared with ANC. The IRF is not affected by infection, is easily measured, and inexpensive; thus, it is a reliable parameter to evaluate bone marrow reconstitution.

Intensive care unit management of patients with newly diagnosed acute myeloid leukemia with no organ failure.

Patients with acute myeloid leukemia (AML) may present with early complications from sepsis or leukemic infiltration. Benefits from early in-intensive care unit (ICU) hematological management was evaluated in 42 adults with newly diagnosed AML with hematological risk of early death (age 46 years, French-American-British [FAB] M4/5 58%, leukocytes 103 × 10(9)/L) first admitted to the ICU without immediate life support (early-ICU). Controls were 42 patients primarily admitted to hematology wards, matched for age, leukocytes and FAB subtype. Twenty (47.6%) control patients were subsequently admitted to the ICU (late-ICU). Late-ICU patients presented with increased respiratory and cardiac rates, decreased oxygen saturation (SpO(2)) and blood pressure, at hospital admission. Late-ICU admission resulted in increased use of mechanical ventilation (60% vs. 33%) and vasopressors (60% vs. 16%), longer ICU stay (9 [6-25] vs. 5 [2-9] days) and decreased ICU survival (65% vs. 79%). Direct admission to the ICU of patients with high-risk AML with physiological disturbances but no organ dysfunction is associated with improved outcomes.

Adult leukemic synovitis is associated with leukemia of monocytic differentiation.

BACKGROUND: Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse. METHODS: A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy. RESULTS: A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis. CONCLUSIONS: Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.

Successful treatment with imatinib mesylate in a case of minor BCR-ABL-positive acute myelogenous leukemia.

Philadelphia (Ph) chromosome-positive acute myelogenous leukemia (AML) is a rare disease that is resistant to conventional antitumor chemotherapy and has a poor prognosis. We describe a case of Ph chromosome-positive AML in which imatinib mesylate was used and a favorable outcome was obtained.A 64-year-old man was found to have Ph chromosome-positive, minor BCR-ABL-positive AML. Remission could not be induced by remission induction therapy with antitumor agents. Because the patient had a serious concomitant infectious disease, administration of 600 mg/day of imatinib mesylate, a specific inhibitor of BCR-ABL tyrosine kinase, was started after written informed consent was obtained. Complete cytogenetic response (CCR) was achieved without serious adverse events and persisted for more than 1 year. Our results suggested that imatinib mesylate was very useful for treating Ph chromosome-positive AML.

[Expression of NM23-H(1) mRNA in acute leukemia].

OBJECTIVE: To determine the expression of NM23-H(1) gene in acute leukemia(AL) and evaluate the relationship between NM23-H(1) expression and clinical features. METHODS: Expression level of NM23-H(1) mRNA in bone marrow cells was determined in 82 acute leukemia patients and 15 normal subjects with semi-quantitative reverse transcription polymerase chain reaction(RT-PCR). RESULTS: NM23-H(1)/ GAP DH ratio >/= 0.5 was considered to be positive. NM23-H(1) mRNA was negative in all the 15 normal subjects. Expression of NM23-H(1) was positive in 43 of the 56 acute leukemia patients in the first visit, expression range being 0.33 approximately 2.75. There was one positive case in 12 AL patients with complete remission, expression range being 0 approximately 0.63,but there was no positive case in 6 AL patients who had maintained complete remission for more than 6 months, expression range being 0 approximately 0.27. Relapsed cases were all positive with an expression range of 0.76 approximately 1.87. NM23-H(1) expression in patients with initial and relapsed acute leukemia was higher than that in normal subjects (P < 0.01). CONCLUSION: Overexpression of NM23-H(1) mRNA can predict treatment outcome and may be an important prognostic factor.

Leukaemia cutis preceding acute myelomonocytic leukaemia.

We report a case of acute myelomonocytic leukaemia (AMML) who presented with a striking leukaemic infiltration in the frontal area of the scalp that was also rapidly followed by infiltrates in other sites of the skin, mainly in the upper thoracic wall. Leukaemic skin infiltration developed independently of his haematological status; nevertheless, he rapidly progressed to acute leukaemia. We emphasise the importance of early recognition and identification of such lesions with a subsequent early application of systematic antileukaemic therapy.

5q- syndrome in a child.

A boy aged 8 years, 10 months presented with refractory anemia. Bone marrow investigation revealed monolobular megakaryocytes. Cytogenetic analysis showed a clonal abnormality: 46, XY, del(5)(q14q32). This is the youngest individual ever reported with this disorder. A year after diagnosis, while on treatment with human recombinant erythropoietin, the bone marrow showed an excess of blasts. No bone marrow donor could be found. Transformation to acute myelomonocytic leukemia occurred 3 months later. In spite of intensive chemotherapy, the child died of progressive disease with massive splenomegaly and jaundice. The case illustrates that the 5q- syndrome can occur de novo in children. The outcome in this child was poor, which may reflect a difference from the adult 5q- syndrome or may possibly be related to the erythropoietin the child received.

Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis.

A case of an acute non-lymphocytic leukemia of M4 type with a supernumerary isochromosome (4p) in 100% of the initial bone marrow metaphase cells is reported. The origin of the extra chromosome is verified by the fluorescence in situ hybridization technique using a whole chromosome 4 painting probe. A possible favorable prognosis of the ANLL-M4 case showing a supernumerary isochromosome (4p) is cautiously emphasized.

AML M1 and M2 with eosinophilia and AML M4Eo: diagnostic and clinical aspects.

AML with eosinophilia belongs to the morphologic cytogenetic entity M1/M2 t(8;21) with the involvement of the genes AML1/ETO. These eosinophils differ only slightly from normal eosinophils with one rare exception i.e. Auer rods in eosinophils which has only been found on peroxidase staining: This subtype belongs to the good prognosis group of AML. AML with inv(16) (mostly M4Eo) per se is a morphologic-cytogenetic entity with inv(16),--rarely t(16;16), and the genes MYL 11/CBF beta involved. The eosinophils show special abnormalities. AML with inv(16) also belongs to the good prognosis group of AML.

[Paraneoplastic edema syndromes in acute myelomonocytic leukemia: role of TNF-alpha and IL-6?]. / Syndrome oedémateux paranéoplasique au cours d'une leucémie aiguë myélomonocytaire: rôle du TNF alpha et de l'IL-6?

We report the case of a 56 year-old man in remission of a Hodgkin's disease who had an acute myelomonocytic leukemia with major edemas. Chemotherapy temporarily allowed a concomitant regression of edemas, hyperleukocytosis and tumor necrosis factor and interleukin-6 levels which were initially elevated. We discuss the role of these two cytokines in endothelium permeability disorders.

Alpha (p55) and beta (p75) chains of the interleukin-2 receptor are expressed by AML blasts.

In the present study, we have investigated the leukemic cells obtained from 16 patients with acute myeloid leukemia (AML) at diagnosis for the membrane expression of p55 (alpha) and p75 (beta) interleukin-2 receptor (IL-2R) chains using specific monoclonal antibodies (mAbs), as well as for the presence of their transcripts using Northern blot analysis. In addition, immunoprecipitation of the p75 membrane molecule with TU27 and Mik-beta 1 mAbs was carried out in selected cases. The p75 IL-2R beta transcripts were detected in all cases, whereas the membrane p75 molecule was demonstrable by flow cytometry in three cases. However, data from the immunoprecipitation analysis suggest that the lack of the p75 IL-2R detection by flow cytometry might be caused by the low density of molecules per cell rather than the fact that the specific mRNA is not translated into the p75 surface molecule. In addition, a consistent membrane positivity with an anti-p55/CD25 mAb, present on fresh uncultured blasts in 37.5% of the cases, became detectable after short-term culture in 75% of cases. In each individual case, a strict correlation was found between membrane CD25 reactivity and the expression of p55 mRNA. Taken together, our data suggest that the expression of both alpha (p55) and beta (p75) IL-2R molecules is a common feature of leukemic cells in AML, and provide new arguments for reassessing the possible role of IL-2 in leukemic growth.

Inverse ratio ventilation in ARDS. Improved oxygenation without autoPEEP.

Inverse ratio ventilation and related ventilatory modes (eg, pressure release ventilation) have been applied to patients with the adult respiratory distress syndrome (ARDS) with apparent beneficial effects on arterial oxyhemoglobin saturation. While several mechanisms of improved gas exchange have been postulated, many intensive care physicians believe that the development of occult PEEP (autoPEEP; intrinsic PEEP) leads to the observed rise in oxygen saturation. We report here our findings in a patient whose improved oxygenation on inverse ratio ventilation could not be attributed to autoPEEP.

[Changes in the functional status of the myocardium in acute leukemia patients]. / Izmeneniia funktsional'nogo sostoianiia miokarda u bol'nykh ostrym leikozom.

The functional state of the myocardium was evaluated in 45 patients with acute leucosis. The physical, electrocardiographic and echocardiographic indices were analyzed. It was found that 40% of patients with acute leucosis in the primary-active phase showed a hypokinetic type of circulation. Revealed were prognostically unfavourable factors--leucocytes with marked blastosis in the peripheral blood and myelogram as well as thrombocytopenia that are of significance in the pathogenesis of myocardial involvement. Cardiotoxic doses of rubomycin were found that lead to lesions of the myocardium and formation of chronic cardiopathy. The authors discuss the pathogenetic mechanisms leading to deterioration of the contractile function of the myocardium, reduction of the stroke volume and reorganization of the central hemodynamics according to the hypokinetic type. Echocardiography allowed to reveal early signs of involvement of the myocardium and to institute early treatment effecting different links of pathogenesis and increase the efficiency of acute leucosis therapy.

What's new in the causes of hemorrhage in acute myelogenous leukemia?

Hemorrhages in AML are still a major problem, although not the most important and different factors are involved in its genesis. The causes that predispose an AML patient to bleed will be reviewed, the hypotheses concerning the coagulation disorder specially found in the FAB M3 type will be discussed and the increasingly recognized role of plasminogen activators and enzymes released from blasts will be emphasized.

Down-regulation of insulin receptors is related to insulin internalization.

In the present study, we have tested the influence of inhibition of endocytosis by hypertonic medium on the regulation of cell surface insulin receptors. We show that active internalization of 125I-insulin is markedly inhibited by hypertonic media and that, in parallel, cell surface invaginations are significantly diminished. These two events are accompanied by a marked inhibition of cell surface insulin receptor down-regulation. These data provide further strong evidence that receptor-mediated endocytosis is the major mechanism by which insulin receptors are regulated at the surface of target cells.

Multivariate analysis of prognostic factors in acute myeloid leukemia: value of clonogenic leukemic cell properties.

The initial clinical and biological parameters, including clonogenic leukemic cell (CFU-L) assay, were reviewed for their prognostic significance in a cohort of 188 adult patients with newly diagnosed untreated acute myeloid leukemia (AML). Almost all patients received induction therapy with daunorubicin (DNR) and cytarabine (Ara-C) according to the European Organization for Research and Treatment of Cancer (EORTC) AML 5 to AML 9 trials. Bone marrow samples from 116 representative patients were obtained for CFU-L assay with an efficiency percentage of 89.6%; 76 patients had a measurement of the CFU-L self-renewal capacity (second plating efficiency [PE2]) and 91 patients had CFU-L inhibition test after exposure to DNR and/or Ara-C. The prognostic significance of parameters such as age, hematological antecedent, WBC count, liver enlargement, and Auer rods is confirmed in the present study. Moreover, high platelet and polymorphonuclear counts appeared to be related to resistance to induction course. However, through multivariate analysis, CFU-L sensitivity to drugs and self-renewal capacity appeared to be major independent prognostic factors in AML. A low CFU-L inhibition in the presence of the DNR and Ara-C combination correlates with a poorer complete remission (CR) rate, but not with CR duration. Patients with the lower PE2 values experienced both higher CR rate and longer CR duration. The practical interest of CFU-L study remains to be defined but, at least, PE2 measurement could be considered in the future as a major variable in determining therapeutic aggressiveness.

[Systemic oxygen transport in patients with myelotoxic agranulocytosis]. / Sistemnyi transport kisloroda u bol'nykh s mielotoksicheskim agranulotsitozom.

The paper presents data on central hemodynamics, blood pulmonary shunting and evaluation of oxygen transport in 30 patients with myelotoxic agranulocytosis. In early agranulocytosis (fourteen cases) there was evidence of a drastic increase in pulmonary shunting, reduced stroke and cardiac indices, oxygen transport and its tissue utilization. By day 5-6 the disturbed parameters returned to normal values. It is noted that a phasic course of agranulocytosis implies time-related differential therapy.