Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial.

BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 ± 8% vs. 81 ± 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 ± 8% vs. 14 ± 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 ± 12% vs. 92 ± 1%, p=0.0081), but no increased CIR (10 ± 10% vs. 6 ± 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 ± 11% vs. 78 ± 2%, p=0.0077) and CIR (44 ± 11% vs. 20 ± 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.

Three-dimensional dentoskeletal changes following minimally invasive surgically assisted rapid palatal expansion: a prospective study.

Dentoskeletal changes in minimally invasive surgically assisted rapid palatal expansion (SARPE) were evaluated using cone beam computed tomography (CBCT). This was a prospective study of 30 patients who underwent minimally invasive SARPE performed under local anaesthesia plus sedation by the same surgeon, in an ambulatory setting. Pre- and postoperative CBCT images were obtained for each patient. A statistically significant increase in the linear transverse dimensions of the maxilla occurred systematically. In the canine region, a mean increase of 5.84 mm occurred at the apex level and 7.82 mm at the crown level. These dimensions were 4.83 mm and 7.68 mm, respectively, in the molar region. The cross-sectional area of the maxilla increased by a mean 12.9 mm2 at the palate level and 23.3 mm2 at the crown level. Dental inclination to the buccal aspect was detected (mean 6.1° at the canines and 8.4° at the first molars). The alveolar process tipped buccally 10° at the molar level. Nasal width increased a mean of 3.0 mm at the canine level. Through a three-dimensional analysis, this study found that minimally invasive SARPE was effective in the correction of transverse maxillary discrepancies> 5 mm in non-growing patients. Although dental inclination to the buccal aspect occurred, significant expansion of the maxilla at the skeletal and dentoalveolar levels was confirmed.

Variation between natural head orientation and Frankfort horizontal planes in orthognathic surgery patients: 187 consecutive cases.

The purpose of this study was to assess the relationship between the Frankfort horizontal (FH) and natural head orientation (NHO), their correlation between patients' malocclusion, and the impact of counterclockwise rotation (CCW) on the FH-NHO angle variation after orthognathic surgery. An evaluation of 187 consecutive patients was performed at the Maxillofacial Institute (Teknon Medical Center, Barcelona). FH-NHO° was measured pre- and postoperatively at 1 and 12 months, after three-dimensional (3D) superimposition using a software (Dolphin®). Patients were classified as follows: 3.2%, 48.7% and 48.1%, class I, II and III, respectively. Baseline FH-NHO° was significantly positive for patients with dentofacial deformities (2.73°±4.19 (2.12-3.33°, P<0.001). The impact of orthognathic surgery in FH-NHO° was greater in class II when compared with class III patients, with a variation of 2.04°±4.79 (P<0.001) and -1.20°±3.03 (P<0.001), respectively. FH-NHO° increased when CCW rotational movements were performed (P=0.006). The results of this study suggest that pre- and postoperative NHO differs from FH in orthognathic patients. The angle between FH and NHO is significantly larger in class III than in class II patients at baseline, which converges after orthognathic surgery when CCW rotation is performed. Therefore, NHO should be used as the real horizontal plane when planning for orthognathic surgery.

Antibiotic prophylaxis in orthognathic surgery: an overview of systematic reviews.

The purpose of this overview was to assess different antibiotic regimens used in orthognathic surgery and to establish an evidence-based protocol so that beneficial and adverse effects can be determined. A comprehensive literature search for systematic reviews and/or meta-analyses was conducted in MEDLINE (PubMed), EMBASE, and the Cochrane Library until March 2020. Grey literature was investigated in Google Scholar, and a manual search was done of references lists. Two meta-analyses and four systematic reviews met the inclusion criteria. The AMSTAR-2-tool was used to ascertain the potential risk of bias in the included studies, which presented moderate to high methodological quality. Lower infection rates were associated with long-term therapies of penicillin, cefazolin-cephalexin, and amoxicillin-clavulanic-acid, with rates varying from 0% - 3.13%. Higher rates were reported in placebo groups (52.6%) and short-term penicillin therapy (60%). Side effects were reported with cefazolin, clindamycin, and penicillin therapies, including nausea, pain, swelling, headache, vomiting, and skin rash. Evidence suggests that long-term antibiotics can reduce the risk of a surgical site infection (SSI) in orthognathic surgery, but there is uncertainty regarding the effects of one dose of antibiotics preoperatively versus short-term antibiotics. In the same way, intravenous penicillin, cefazolin, clindamycin, and amoxicillin-clavulanic acid kept the infection rates associated with bimaxillary procedures under 3.5%.

Nasolabial soft tissue effects of segmented and non-segmented Le Fort I osteotomy using a modified alar cinch technique-a cone beam computed tomography evaluation.

The aim of this study was to verify soft tissues changes and the effect of a minimally invasive surgical technique in the nasolabial region after segmented and non-segmented Le Fort I osteotomy, using cone beam computed tomography (CBCT) evaluation of three-dimensional (3D) volume surfaces. Two groups were evaluated: group 1, bimaxillary surgery with maxillary segmentation (n=40); group 2, bimaxillary surgery without maxillary segmentation (n=40). In both groups, a specific alar cinching technique was used to control nasal base broadening. CBCT evaluation was performed at three different treatment time points: T0, 1 month before surgery; T1, 1 month after surgery; T2, 1year after surgery. The results showed statistically significant differences in the nasolabial area (P<0.001). For group 1, the mean change in alar base width (Alinf-Alinf) was 1.31±1.40mm at T1 and 0.93±1.77mm at T2; for group 2 these values were 1.12±2.01mm at T1 and 0.54±1.54mm at T2. For group 1, the mean changes in inter-alar width (Al-Al) were 1.68±1.46mm at T1 and 1.49±1.33mm at T2; for group 2, they were 2.22±1.93mm at T1 and 1.34±1.79mm at T2. The alar cinch technique proposed here appears to be effective in controlling nasolabial soft tissue widening.

Sporadic hypercalcitoninemia: clinical and therapeutic consequences.

'Calcitonin screening' is not accepted as the standard of care in daily practice. The clinical and surgical consequences of 'calcitonin screening' in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic ('carcinoma in situ'). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.

Three-dimensional analysis of nasolabial soft tissue changes after Le Fort I osteotomy: a systematic review of the literature.

A systematic review was conducted to investigate the three-dimensional (3D) effect of Le Fort I osteotomy on the nasolabial soft tissues. The literature search was conducted using the MEDLINE (accessed via PubMed), Embase, and Cochrane electronic databases until January 2018. A total of 333 studies were identified (PubMed, n=292; Embase, n=41; Cochrane Library, n=0). Seventeen met the inclusion criteria. The studies were essentially retrospective. The risk of bias was considered high in 15 studies, medium in one study, and low in one study. 3D soft tissue analysis was performed at least 6months after surgery (mean 8.3months). The main image acquisition technique reported was cone beam computed tomography (CBCT), associated or not with 3D photography. Approximately 50% of the studies performed two-jaw surgery, 25% performed maxillary surgery only, and the other 25% included heterogeneous intervention groups. The most reported nasolabial changes were anterior and lateral movements of the nasomaxillary soft tissues and upper lip, together with anterior and superior movement of the nasal tip. The alar cinch suture and V-Y closure technique seemed to have little effect in counteracting the undesirable postoperative nasolabial changes. CBCT superimposition presented a reliable 3D assessment for simultaneous measurement of skeletal and soft tissue changes.

Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia.

BACKGROUND: Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML). PATIENTS AND METHODS: We treated six patients with imatinib-resistant CML in haematological relapse (leukocytes > 20,000 microL(-1)) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose-adjustment allowed to reach a target rapamycin serum concentration of 10-20 pg mL(-1). RESULTS: A major leukocyte response with decrease to less than 10,000 microL(-1) was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by (3)H-thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib-resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors. CONCLUSIONS: Rapamycin shows antileukaemic effects in imatinib-resistant CML in vitro and in vivo. Larger trials with rapamycin or rapamycin-derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.

Comorbidity predicts survival in myelodysplastic syndromes or secondary acute myeloid leukaemia after allogeneic stem cell transplantation.

BACKGROUND: Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT). PATIENTS AND METHODS: We examined the overall survival (OS) and underlying risk factors in 45 adult patients with MDS (n = 38), chronic myelomonocytic leukaemia (n = 1), or secondary acute myeloid leukaemia (AML) arising from MDS (n = 6), who underwent allogeneic SCT at our Institution. RESULTS: With a median follow-up of 37 months, OS for all patients was 23%, post-transplant relapse occurred in 11 patients, and 10 patients died from treatment-related complications. The overall outcome and survival was independent of cytogenetic abnormalities and International Prognostic Scoring System (IPSS). However, we identified comorbidity as defined by the haematopoietic cell transplantation specific comorbidity index (HCT-CI), as a significant adverse prognostic variable in our MDS patients. CONCLUSIONS: Based on these data and similar published data we recommend selecting patients with MDS or secondary AML for SCT according to the presence of comorbidities.

A comparison of neural network approaches for on-line prediction in IGRT.

Image-guided radiation therapy aims to improve the accuracy of treatment delivery by tracking tumor position and compensating for observed movement. Due to system latency it is sometimes necessary to predict tumor trajectory evolution in order to facilitate changes in beam delivery. Neural networks (NNs) have previously been investigated for predicting future tumor position because of their ability to model non-linear systems. However, no attempt has been made to optimize the NN training algorithms, and no mention has been made of potential errors which can be caused by using NNs for extrapolation purposes. In this work, after giving a brief explanation of NN theory, a comparison is made between 4 different adaptive algorithms for training time-series prediction NNs. New error criteria are introduced which highlight error maxima. Results are obtained by training the NNs using previously published data. A hybrid algorithm combining Bayesian regularization with conjugate-gradient backpropagation is demonstrated to give the best average prediction accuracy, whilst a generalized regression NN is shown to reduce the possibility of isolated large prediction errors.

Alveolar corticotomies for accelerated orthodontics: A systematic review.

INTRODUCTION: It has been suggested that alveolar corticotomies may accelerate tooth movement, broaden the scope of malocclusion types that can be treated orthodontically, decrease the need for extractions, and support long-term stability. Several techniques have been proposed, although the indications, ideal design and technical characteristics, potential complications, and objective clinician and patient satisfaction remain unclear. This systematic review aimed to provide scientific support to validate alveolar corticotomies as a reliable approach to accelerated orthodontics. MATERIAL & METHODS: A literature search was conducted using MEDLINE (via PubMed), Cochrane, and EMBASE electronic databases until December, 2016. Articles written in any language other than English, Spanish, French, German, and Portuguese were excluded. Randomized controlled trials, controlled clinical trials, and case series involving healthy adult patients, with a sample size of at least 5 patients, and using alveolar corticotomy techniques were included. Two reviewers extracted the data independently. RESULTS: Three randomized clinical trials, 2 prospective randomized clinical trials, 6 case series and 1 randomized controlled split-mouth study were included. No clinical trials were retrieved. Mean total treatment time in corticotomy-facilitated orthodontic cases was 8.85 months (range, 4-20 months); control groups treatment duration was 16.4 months (range, 7.8-28.3 months). Complications such as pain, swelling, and dentin hypersensitivity were reported. Few studies mentioned patient/clinician satisfaction. The faster and less invasive procedures appeared to be well tolerated. However, the methodological quality of the selected studies was low, with only low to moderate scientific evidence. CONCLUSIONS: Corticotomy-facilitated orthodontics resulted in decreased treatment time. Few complications and low morbidity were found. More solid evidence-based research is required to support these results.

Clinical and prognostic significance of histamine monitoring in patients with CML during treatment with imatinib (STI571).

BACKGROUND: Although imatinib is highly effective in chronic myeloid leukemia (CML), drug-resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during treatment with imatinib is important. However, most MRD-parameters are expensive and require special technology. We determined the value of histamine as MRD-marker in CML. PATIENTS AND METHODS: Histamine levels were measured serially in whole blood samples before and during imatinib therapy in 80 CML patients by radioimmunoassay. RESULTS: Histamine levels were highly upregulated in CML at diagnosis compared to healthy controls, and correlated with the presence of basophils. During treatment with imatinib, histamine levels decreased and returned to normal levels in those achieving a complete cytogenetic response (CCR). Loss of CCR during therapy was invariably accompanied by an increase in histamine. Moreover, a histamine level of >100 ng/ml three or six months after start of imatinib was associated with a significantly reduced probability of survival (p<0.05). Whereas basophils were found to correlate well with histamine during imatinib, no correlations were found between histamine and Ph+ metaphases or histamine and BCR/ABL. CONCLUSION: Histamine-monitoring during treatment with imatinib is of prognostic significance.

The MLL recombinome of acute leukemias.

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004.

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

Small supernumerary marker chromosomes--progress towards a genotype-phenotype correlation.

Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they are too small to be characterized for their chromosomal origin by traditional banding techniques, but require molecular cytogenetic techniques for their identification. Apart from the correlation of about one third of the sSMC cases with a specific clinical picture, i.e. the i(18p), der(22), i(12p) (Pallister Killian syndrome) and inv dup(22) (cat-eye) syndromes, most of the remaining sSMC have not yet been correlated with clinical syndromes. Recently, we reviewed the available >1600 sSMC cases (Liehr T, sSMC homepage: http://mti-n.mti.uni-jena.de/~huwww/MOL_ZYTO/sSMC.htm). A total of 387 cases (including the 45 new cases reported here) have been molecularly cytogenetically characterized with regard to their chromosomal origin, the presence of euchromatin, heterochromatin and satellite material. Based on analysis of these cases we present the first draft of a basic genotype-phenotype correlation for sSMC for all human chromosomes apart from the chromosomes Y, 10, 11 and 13.

MDR1 gene expression and treatment outcome in acute myeloid leukemia.

To prospectively assess the role of MDR1 gene expression in patients with de novo acute myeloid leukemia (AML), levels of MDR1 RNA in blast cells were determined at diagnosis and correlated with treatment outcome in 63 patients. MDR1 RNA levels were negative in 29% and positive in 71% of the patients. The complete remission rate in response to induction chemotherapy was 89% for MDR1 RNA-negative patients and 53% for MDR1 RNA-positive patients (P = .008). Expression of the MDR1 gene was observed in most patients who died early or had resistant disease. Kaplan-Meier curves revealed a decrease in both disease-free survival and overall survival of patients with detectable MDR1 gene expression compared with the disease-free survival and overall survival of MDR1 RNA-negative patients (P = .029 and P = .009, respectively). These data indicate that MDR1 gene expression is an unfavorable prognostic factor and suggest that multidrug resistance is important in AML.

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23).

We report the cloning and characterization of the entire AFX gene which fuses to MLL in acute leukemias with a t(X;ll)(q13;q23). AFX consists of two exons and encodes for a protein of 501 amino acids. We found that normal B- and T-cells contain similar levels of AFX mRNA and that both the MLL/AFX as well as the AFX/MLL fusion transcripts are present in the cell line and the ANLL sample with a t(X;11)(q13;q23). The single intron of the AFX gene consists of 3706 nucleotides. It contains five simple sequence repeats with lengths of at least 12 bps, a chi-like octamer sequence (GCA/TGGA/TGG) and several immunoglobulin heptamer-like sequences (GATAGTG) that are distributed throughout the entire AFX intron sequence. In the KARPAS 45 cell line the breakpoints occur at nucleotides 2913/2914 of the AFX intron and at nucleotides 4900/4901 of the breakpoint cluster region of the MLL gene. The AFX protein belongs to the forkhead protein family. It is highly homologous to the human FKHR protein, the gene of which is disrupted by the t(2;13)(q35;q14), a chromosome rearrangement characteristic of alveolar rhabdomyosarcomas. It is noteworthy that the t(X;11)(q13;q23) in the KARPAS 45 cell line and in one acute nonlymphoblastic leukemia (ANLL) disrupts the forkhead domain of the AFX protein exactly at the same amino acids as does the t(2;13)(q35;q14) in case of the FKHR protein. In addition, the 5'-part of the AFX protein contains a conserved hexapeptide motif (QIYEWM) that is homologous to the functionally important conserved hexapeptide QIYPWM upstream of the homeobox domain in Hox proteins. This motif mediates the co-operative DNA binding of Pbx family members and Hox proteins and, therefore, plays an important role in physiologic and oncogenic processes. In acute leukemias with a t(X;11)(q13;q23), this hexapeptide motif is separated from the remaining forkhead domain within the AFX protein. The predicted amino acid sequence of AFX differs significantly from the partial AFX protein sequence published previously (Genes, Chromosomes and Cancer, 1994, 11, 79-84). This discrepancy can be explained by the occurrence of two sequencing errors in the earlier work at nucleotide number 783 and 844 (loss of a cytosine residue or guanosine residue, respectively) that lead to two reading frame shifts.

Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL.

Derivative chromosomes of 40 patients diagnosed with t(4;11) acute lymphoblastic leukemia (ALL) were analysed on the genomic DNA level. Chromosomal breakpoints were identified in most cases within the known breakpoint cluster regions of the involved MLL and AF4 genes. Due to our current knowledge of the primary DNA sequences of both breakpoint cluster regions, specific features were identified at the chromosomal fusion sites, including deletions, inversions and duplications of parental DNA sequences. After separation of all t(4;11) leukemia patients into two age classes (below and above 1 year of age), the analysis of chromosomal fusion sites revealed significant differences in the distribution of chromosomal breakpoints and led to the definition of two hotspot areas within the MLL breakpoint cluster region. This may point to the possibility of different age-linked mechanisms that were leading to t(4;11) chromosomal translocations.