Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia.

Richter syndrome (RS) is associated with poor outcome. The prognosis of patients with histologically aggressive chronic lymphocytic leukemia (CLL), or HAC, has not been studied. We aimed to correlate 2-deoxy-2-[(18)F]fluoroglucose/positron emission tomography (FDG/PET) data, histological diagnosis, clinical characteristics, and survival in patients with CLL. A total of 332 patients with CLL were histologically classified as: 95 RS, 117 HAC, and 120 histologically indolent CLL (HIC). HAC and RS patients had higher maximum standardized uptake value (SUVmax), more frequent constitutional symptoms, poorer performance status (PS), lower hemoglobin and platelets, and higher lactate dehydrogenase and ß-2-microglobulin. An SUVmax ≥10 strongly correlated with mortality (overall survival [OS], 56.7 vs 6.9 months in patients with SUVmax <10 vs ≥10). Survival of patients with RS and HAC was similar among patients with SUVmax <10 or ≥10. SUVmax ≥10, PS ≥2, bulky disease, and age ≥65 were independently associated with shorter OS. In patients undergoing both fine-needle aspiration and biopsy, the former proved diagnostically inadequate in 23%, 29%, and 53% of HIC, HAC, and RS, respectively. FDG/PET is a useful diagnostic tool in patients with CLL and suspected transformation. Patients with HAC show different characteristics and worse prognosis compared with those with HIC. Patients with different CLL phases, but similar SUVmax have similar outcome. Tissue biopsy should be preferred for diagnosing RS.

CT-Guided Wire Localization for Involved Axillary Lymph Nodes After Neo-adjuvant Chemotherapy in Patients With Initially Node-Positive Breast Cancer.

Resection of biopsy-proven involved axillary lymph nodes (iALNs) is important to reduce the false-negative rates of sentinel lymph node (SLN) biopsy after neo-adjuvant chemotherapy (NAC) in patients with initially node-positive breast cancer. Preoperative wire localization for iALNs marked with clips placed during biopsy is a technique that may help the removal of iALNs after NAC. However, ultrasound (US)-guided localization is often difficult because the clips cannot always be reliably visible on US. Computed tomography (CT)-guided wire localization can be used; however, to date there have been no reports on CT-guided wire localization for iALNs. The aim of this study was to describe a series of patients who received CT-guided wire localization for iALN removal after NAC and to evaluate the feasibility of this technique. We retrospectively analyzed five women with initially node-positive breast cancer (age, 41-52 years) who were scheduled for SLN biopsy after NAC and received preoperative CT-guided wire localization for iALNs. CT visualized all the clips that were not identified on post-NAC US. The wire tip was deployed beyond or at the target, with the shortest distance between the wire and the index clip ranging from 0 to 2.5 mm. The total procedure time was 21-38 minutes with good patient tolerance and no complications. In four of five cases, CT wire localization aided in identification and resection of iALNs that were not identified with lymphatic mapping. Residual nodal disease was confirmed in two cases: both had residual disease in wire-localized lymph nodes in addition to SLNs. Although further studies with more cases are required, our results suggest that CT-guided wire localization for iALNs is a feasible technique that facilitates identification and removal of the iALNs as part of SLN biopsy after NAC in situations where US localization is unsuccessful.

Initial results with preoperative tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast cancer patients.

BACKGROUND: Pretreatment evaluation of axillary lymph nodes (ALNs) and marking of biopsied nodes in patients with newly diagnosed breast cancer is becoming routine practice. We sought to test tattooing of biopsied ALNs with a sterile black carbon suspension (Spot™). The intraoperative success of identifying tattooed ALNs and their concordance to sentinel nodes was determined. METHODS: Women with suspicious ALNs and newly diagnosed breast cancer underwent palpation and/or ultrasound-guided fine needle aspiration or core needle biopsy, followed by injection of 0.1 to 0.5 ml of Spot™ ink into the cortex of ALNs and adjacent soft tissue. Group I underwent surgery first, and group II underwent neoadjuvant therapy followed by surgery. Identification of black pigment and concordance between sentinel and tattooed nodes was evaluated. RESULTS: Twenty-eight patients were tattooed, 16 in group I and 12 in group II. Seventeen cases had evidence of atypia or metastases, 8 (50 %) in group I and 9 (75 %) in group II. Average number of days from tattooing to surgery was 22.9 (group I) and 130 (group II). Black tattoo ink was visualized intraoperatively in all cases, except one case with microscopic black pigment only. Fourteen group I and 10 group II patients had black pigment on histological examination of ALNs. Sentinel nodes corresponded to tattooed nodes in all except one group I patient with a tattooed non-sentinel node. CONCLUSION: Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.

High fluorescence in situ hybridization percentage of deletion 11q in patients with chronic lymphocytic leukemia is an independent predictor of adverse outcome.

We have analyzed patients with previously untreated chronic lymphocytic leukemia with del11q fluorescence in situ hybridization (FISH) abnormality (n = 196) in this study. Detection of the 11q22.3 used a multicolor FISH technique. Patients with del11q fell into two major FISH subsets-sole del11q (n = 64) and del11q with del13q (n = 132). FISH subsets were compared using the median del11q FISH% (>58%, high vs. ≤58%, low). Overall survival (OS) and time to first treatment (TTFT) were estimated using Kaplan-Meier plots (log rank). Multivariate analysis was performed to assess the association between FISH% of del11q and outcomes. Patients with sole del11q were similar to del11q with del13q in terms of TTFT and OS. Patients with high FISH% of del11q had significantly shorter OS and TTFT as compared with patients with low FISH%, particularly in sole del11q; this negative impact of high FISH% of del11q on OS and TTFT was diminished with coexistent del13q. In multivariate analysis, high FISH% of del11q was a significant predictor for shorter OS and TTFT. A comparison of these del11q subsets with a separate cohort of (n = 673) previously untreated patients with sole del13q showed that the high FISH% del11q cohort had a significantly shorter TTFT and OS. In addition, bulky disease by physical examination or computed tomography imaging was infrequent at presentation in patients with del11q. High FISH% of del11q can reliably discriminate higher risk patients with chronic lymphocytic leukemia. Presence of coexistent del13q should be accounted for while prognosticating patients with del11q.

Antibiotic prescribing practices of medical doctors in a resource-limited setting and the influence of individual perceptions and stewardship support: a survey in three tertiary hospitals in Vietnam.

Objectives: To understand antibiotic prescribing and influencing factors to inform antimicrobial stewardship (AMS) interventions to reduce unwanted consequences of antibiotic use in hospitals in Vietnam, a lower-middle-income country in Asia. Methods: We conducted a cross-sectional study of doctors at three tertiary hospitals using non-probability convenience sampling, through a paper-based (Hospitals 1 and 2) or electronic (Hospital 3) survey. Questions included items on perceptions regarding antibiotic resistance and AMS, prescribing practices, knowledge, demographics and training. We used principal components analysis and mixed-effects models to examine practices and identify influencing factors. Results: Among 314 surveyed participants, 61%, 57% and 59% in Hospitals 1, 2 and 3, respectively, felt certain about the appropriateness of their antibiotic prescriptions. In total, 9% reported sometimes prescribing antibiotics when not needed to meet patients' expectations, and 13% reported doing so to avoid perceived complications. Higher prescribing confidence was found among those with positive perceptions about AMS (P < 0.0001), whereas negative perceptions about colleagues' practices reduced this confidence (P < 0.0001). Individual preference for branded antibiotics was associated with more unnecessary prescribing whereas having higher prescribing confidence decreased the habits of prescribing when not needed. Conclusions: This study provides important implications for design of hospital interventions to address influencing factors on antibiotic prescribing in Vietnam and similar resource-limited settings. Specific interventions should target improving knowledge through education and training for doctors, enhancing the support from the AMS team, and promoting guidelines and policies for appropriate antibiotic use in hospital.

Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities: A multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: Overall IgG seroprevalence was 99.7% (95%CI: 99.2-99.9) for measles and 83.6% (95%CI: 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed postvaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Development of Efficient Sodium Alginate/Polysuccinimide-Based Hydrogels as Biodegradable Acetaminophen Delivery Systems.

Efficient drug delivery systems are essential for improving patient outcomes. Acetaminophen (AP), which is a kind of oral administration, is a commonly used pain reliever and fever reducer. However, oral administration carries various health risks, especially overdose and frequent use; for instance, AP is administered approximately 4 times per day. Therefore, the aim of this study is to develop an efficient delivery system for once-daily administration by combining sodium alginate and polysuccinimide (PSI) hydrogels to delay the release of analgesic AP. PSI is a biodegradable polymer that can be used safely and effectively in drug delivery systems because it is eliminated by hydrolysis in the intestine. The use of PSI also improves the mechanical properties of hydrogels and prolongs drug release. In this study, hydrogel characterizations such as mechanical properties, drug dissolution ability, and biodegradability were measured to evaluate the hydrolysis of PSI in the intestine. Based on the results, hydrogels could be designed to improve the structural mechanical properties and to allow the drug to be completely dissolved, and eliminated from the body through PSI hydrolysis in the intestines. In addition, the release profiles of AP in the hydrogels were evaluated, and the hydrogels provided continuous release of AP for 24 h. Our research suggests that sodium alginate/PSI hydrogels can potentially serve as biodegradable delivery systems for AP. These findings may have significant implications for developing efficient drug delivery systems for other classes of drugs.

Impact of the COVID-19 Pandemic on Breast Imaging Education.

OBJECTIVE: To determine the impact of the COVID-19 pandemic on breast imaging education. METHODS: A 22-item survey addressing four themes during the early pandemic (time on service, structured education, clinical training, future plans) was emailed to Society of Breast Imaging members and members-in-training in July 2020. Responses were compared using McNemar's and Mann-Whitney U tests; a general linear model was used for multivariate analysis. RESULTS: Of 136 responses (136/2824, 4.8%), 96 U.S. responses from radiologists with trainees, residents, and fellows were included. Clinical exposure declined during the early pandemic, with almost no medical students on service (66/67, 99%) and fewer clinical days for residents (78/89, 88%) and fellows (48/68, 71%). Conferences shifted to remote live format (57/78, 73%), with some canceled (15/78, 19%). Compared to pre-pandemic, resident diagnostic (75/78, 96% vs 26/78, 33%) (P < 0.001) and procedural (73/78, 94% vs 21/78, 27%) (P < 0.001) participation fell, as did fellow diagnostic (60/61, 98% vs 47/61, 77%) (P = 0.001) and procedural (60/61, 98% vs 43/61, 70%) (P < 0.001) participation. Most thought that the pandemic negatively influenced resident and fellow screening (64/77, 83% and 43/60, 72%, respectively), diagnostic (66/77, 86% and 37/60, 62%), and procedural (71/77, 92% and 37/61, 61%) education. However, a majority thought that decreased time on service (36/67, 54%) and patient contact (46/79, 58%) would not change residents' pursuit of a breast imaging fellowship. CONCLUSION: The pandemic has had a largely negative impact on breast imaging education, with reduction in exposure to all aspects of breast imaging. However, this may not affect career decisions.

Adaptations of Breast Imaging Centers to the COVID-19 Pandemic: A Survey of California and Texas.

OBJECTIVE: To determine the early impact of the COVID-19 pandemic on breast imaging centers in California and Texas and compare regional differences. METHODS: An 11-item survey was emailed to American College of Radiology accredited breast imaging facilities in California and Texas in August 2020. A question subset addressed March-April government restrictions on elective services ("during the shutdown" and "after reopening"). Comparisons were made between states with chi-square and Fisher's tests, and timeframes with McNemar's and paired t-tests. RESULTS: There were 54 respondents (54/240, 23%, 26 California, 28 Texas). Imaging volumes fell during the shutdown and remained below pre-pandemic levels after reopening, with reduction in screening greatest (ultrasound 12% of baseline, mammography 13%, MRI 23%), followed by diagnostic MRI (43%), procedures (44%), and diagnostics (45%). California reported higher volumes during the shutdown (procedures, MRI) and after reopening (diagnostics, procedures, MRI) versus Texas (P = 0.001-0.02). Most screened patients (52/54, 96% symptoms and 42/54, 78% temperatures), and 100% (53/53) modified check-in and check-out. Reading rooms or physician work were altered for social distancing (31/54, 57%). Physician mask (45/48, 94%), gown (15/48, 31%), eyewear (22/48, 46%), and face shield (22/48, 46%) use during procedures increased after reopening versus pre-pandemic (P < 0.001-0.03). Physician (47/54, 87%) and staff (45/53, 85%) financial impacts were common, but none reported terminations. CONCLUSION: Breast imaging volumes during the early pandemic fell more severely in Texas than in California. Safety measures and financial impacts on physicians and staff were similar in both states.

Impact of a chemotherapy workload and productivity dashboard on pharmacy technician turnover.

PURPOSE: To describe the methods used in the development of an intravenous chemotherapy workload and productivity dashboard and its impact on symptoms of burnout and technician turnover. SUMMARY: In February 2017, chemotherapy sterile preparation pharmacy technicians reported symptoms of burnout as a result of perceived increase in workload. In response, an i.v. chemotherapy workload and productivity dashboard was developed at an academic medical center to validate workload in comparison to the reported job stress of pharmacy technicians. The dashboard provided pharmacy leadership objective data to validate staff concerns and leveraged lean principles to level-load the work prior to requesting additional full-time equivalents (FTEs) to senior leadership. The rate of turnover of i.v. chemotherapy technicians was assessed before (December 2016-June 2017) and after (July 2017-January 2018) dashboard implementation and approval of an additional i.v. chemotherapy technician FTE. The addition of the new FTE resulted in a decrease in productivity from an average of 106% (range 67%-151%) to 84% (range 65%-110%). The interventions allowed for the ability to leverage a staffing-to-demand model, resulting in the observed improvement in technician symptoms of burnout and a notable decrease in the overall turnover rate of i.v. chemotherapy technicians. CONCLUSION: The i.v. chemotherapy workload and productivity dashboard confirmed frontline staff perception and provided data to support the addition of labor resource and an opportunity to leverage a staffing-to-demand model to decrease symptoms of burnout and technician turnover.

Impact of a quality-assessment dashboard on the comprehensive review of pharmacist performance.

PURPOSE: The impact of a quality-assessment dashboard and individualized pharmacist performance feedback on the adherence of order verification was evaluated. METHODS: A before-and-after study was conducted at a 1,440-bed academic medical center. Adherence of order verification was defined as orders verified according to institution-derived, medication-related guidelines and policies. Formulas were developed to assess the adherence of verified orders to dosing guidelines using patient-specific height, weight, and serum creatinine clearance values from the electronic medical record at the time of pharmacist verification. A total of 5 medications were assessed by the formulas for adherence and displayed on the dashboard: ampicillin-sulbactam, ciprofloxacin, piperacillin-tazobactam, acyclovir, and enoxaparin. Adherence of order verification was assessed before (May 1-July 31, 2015) and after (November 1, 2015-January 31, 2016) individualized performance feedback was given based on trends identified by the quality-assessment dashboard. RESULTS: There was a significant increase in the overall adherence rate postintervention (90.1% versus 91.9%, p = 0.040). Among the 34 pharmacists who participated, the percentage of pharmacists with at least 90% overall adherence increased postintervention (52.9% versus 70.6%, p = 0.103). Time to verification was similar before and after the study intervention (median, 6.0 minutes; interquartile range, 3-13 minutes). The rate of documentation for nonadherent orders increased significantly postintervention (57.1% versus 68.5%, p = 0.019). CONCLUSION: The implementation of the quality-assessment dashboard, educational sessions, and individualized performance feedback significantly improved pharmacist order-verification adherence to institution-derived, medication-related guidelines and policies and the documentation rate of nonadherent orders.

Patient awareness of breast density and interest in supplemental screening tests: comparison of an academic facility and a county hospital.

PURPOSE: The aim of this study was to measure women's knowledge of breast density and their attitudes toward supplemental screening tests in the setting of the California Breast Density Notification Law at an academic facility and a county hospital, serving women with higher and lower socioeconomic status, respectively. METHODS: Institutional review board exemptions were obtained. A survey was administered during screening mammography at two facilities, assessing women's awareness of and interest in knowing their breast density and interest in and willingness to pay for supplemental whole breast ultrasound and contrast-enhanced spectral mammography (CEMG). The results were compared by using Fisher exact tests between groups. RESULTS: A total of 105 of 130 and 132 of 153 women responded to the survey at the academic and county facilities, respectively. Among respondents at the academic and county facilities, 23% and 5% were aware of their breast density, and 94% and 79% wanted to know their density. A majority were interested in supplemental ultrasonography and CEMG at both sites; however, fewer women had a willingness to pay for the supplemental tests at the county hospital compared with those at the academic facility (22% and 70%, respectively, for ultrasound, P < .0001; 20% and 65%, respectively, for CEMG, P < .0001). CONCLUSIONS: Both groups of women were interested in knowing their breast density and in supplemental screening tests. However, women at the county hospital were less willing to incur out-of-pocket expenses, suggesting a potential for a disparity in health care access for women of lower socioeconomic status after the enactment of breast density notification legislation.

Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes.

Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.

Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase.

BACKGROUND: Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy. PATIENTS AND METHODS: We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets < 100 × 10(9)/L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16). RESULTS: The rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs. CONCLUSION: TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.

IRF4 is a suppressor of c-Myc induced B cell leukemia.

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EµMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/-)Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EµMyc mice.

Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam.

Between 1998 and 2007, 42 patients admitted to Choray hospital, Ho Chi Minh City, and to two hospitals in adjacent regions in southern Viet Nam brought the Malayan kraits (Bungarus candidus) that had been responsible for biting them. Half of the patients had been bitten while they were asleep. Fang marks and numbness were the only local features of the bites. Common signs of neurotoxic envenoming included bilateral ptosis, persistently dilated pupils, limb weakness, breathlessness, hypersalivation, dysphonia and dysphagia. Thirty patients (71.4%) required endotracheal intubation of whom all but one were mechanically ventilated. Fourteen patients (33.3%) developed hypertension, 13 (31.0%) shock, 31 (73.8%) hyponatraemia (plasma sodium concentration < 130 mEq/l) and 30 (71.4%) showed evidence of mild rhabdomyolysis (peak plasma creatine kinase concentration 1375 +/- 140 micro/l). None developed acute kidney injury. All the patients were treated with a new monospecific B. candidus antivenom. There were no fatalities. Hyponatraemia has been reported previously in victims of Chinese kraits (Bungarus multicinctus) in northern Viet Nam and rhabdomyolysis in patients envenomed by B. niger in Bangladesh. These features of envenoming pose new problems for the management of krait bite cases in South east Asia and should stimulate a search for the causative venom toxins.

Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression.

Pre-B-cell expansion is driven by signals from the interleukin-7 receptor and the pre-B-cell receptor and is dependent on cyclin D3 and c-Myc. We have shown previously that interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to suppress pre-B-cell proliferation. However, the molecular mechanisms through which Ikaros and Aiolos exert their growth inhibitory effect remain to be determined. Here, we provide evidence that Aiolos and Ikaros bind to the c-Myc promoter in vivo and directly suppress c-Myc expression in pre-B cells. We further show that downregulation of c-Myc is critical for the growth-inhibitory effect of Ikaros and Aiolos. Ikaros and Aiolos also induce expression of p27 and downregulate cyclin D3 in pre-B cells, and the growth-inhibitory effect of Ikaros and Aiolos is compromised in the absence of p27. A time course analysis further reveals that downregulation of c-Myc by Ikaros and Aiolos precedes p27 induction and cyclin D3 downregulation. Moreover, downregulation of c-Myc by Ikaros and Aiolos is necessary for the induction of p27 and downregulation of cyclin D3. Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion.

Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development.

Pre-B lymphocytes consist of 2 distinct cell populations: large pre-B and small pre-B. The large pre-B cells are newly generated pre-B cells that express pre-B-cell receptor (pre-BCR) on the surface and are highly proliferative; small pre-B cells are derived from large pre-B cells that have down-regulated pre-BCR and withdrawn from cell cycle. The molecular events that mediate the transition from cycling pre-B to small, resting pre-B have not been fully elucidated. Here, we show that interferon regulatory factors 4 and 8 (IRF4,8) suppress surrogate light chain expression and down-regulate pre-BCR in pre-B cells. Our studies further reveal that IRF4,8 induce the expression of Ikaros and Aiolos in pre-B cells, and reconstitution of expression of either one is sufficient to suppress surrogate light chain expression and down-regulate pre-BCR in pre-B cells lacking IRF4,8. Interestingly, our results also indicate that pre-B cells undergo growth inhibition and cell-cycle arrest in the presence of IRF4,8. Moreover, we provide evidence that Ikaros and Aiolos are indispensable for the down-regulation of pre-BCR and the cell-cycle withdrawal mediated by IRF4,8. Thus, IRF4,8 orchestrate the transition from large pre-B to small pre-B cells by inducing the expression of Ikaros and Aiolos.

A role for interferon regulatory factor 4 in receptor editing.

Receptor editing is the primary means through which B cells revise antigen receptors and maintain central tolerance. Previous studies have demonstrated that interferon regulatory factor 4 (IRF-4) and IRF-8 promote immunoglobulin light-chain rearrangement and transcription at the pre-B stage. Here, the roles of IRF-4 and -8 in receptor editing were analyzed. Our results show that secondary rearrangement was impaired in IRF-4 but not IRF-8 mutant mice, suggesting that receptor editing is defective in the absence of IRF-4. The role of IRF-4 in receptor editing was further examined in B-cell-receptor (BCR) transgenic mice. Our results show that secondary rearrangement triggered by membrane-bound antigen was defective in the IRF-4-deficient mice. Our results further reveal that the defect in secondary rearrangement is more severe at the immunoglobulin lambda locus than at the kappa locus, indicating that IRF-4 is more critical for the lambda rearrangement. We provide evidence demonstrating that the expression of IRF-4 in immature B cells is rapidly induced by self-antigen and that the reconstitution of IRF-4 expression in the IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, our studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B-cell stage.