ABL1 deletion

In addition, the deletion of Tif1β sensitized BCR::ABL1 KI leukemic cells to dasatinib...TIF1β directly bound to the promoters of proliferation genes, such as FOSL1, in human BCR::ABL1 cells, in which TIF1β and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCR::ABL1 KI cells, Tif1β and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCR::ABL1 KI stem cells and drove the progression of myeloid leukemia.

After considering transplantation, high ECM1 transcription level was not an independent risk factor, although OS was still poor (low vs. high, 71.1% vs. 56.8%, P = 0.038). Our findings suggested that ECM1 may be a potential molecular marker for diagnosis, minimal residual disease (MRD) monitoring, and prognosis prediction of B cell ALL.Trial registration Trial Registration Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTR-OPC-14005546]; http://www.chictr.org.cn .

Additionally, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2, were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1-positive BCP-ALL.

In both cases, the disease was refractory to multiple agents in the recurrent phase after allogeneic hematopoietic cell transplantation. This is a case report of a truncated ABL1 mutation in 2 patients with Ph B-ALL.

The logistics of proceeding to transplant might necessitate consolidation chemotherapy usually involving high dose cytarabine (HiDAC)...Infections included bacteremia from Klebsiella, E. Coli, Proteus, group B strep, vancomycin resistant E. Faecalis, and coagulase negative staph, pneumonia from Klebsiella, urinary tract infections from extended spectrum beta-lactamase resistant E. Coli, Klebsiella, and proteus mirabilis, fungal sinusitis, and Clostridium difficile colitis...HSCT is the sole curative option for high-risk AML patients, and the concept of bridging the period between induction and HSCT with HiDAC consolidation appears to offer no additional benefit compared to IDAC. Moreover, this approach prevents a subset of this population from being fit enough to receive HSCT.

With >2 years of follow-up in the phase 3 ASCEMBL study, asciminib (ASC) has continued to demonstrate superior efficacy vs bosutinib (BOS) in pts with CML-CP after ≥2 prior TKIs, and analysis of cancer gene somatic mutations in this population has the potential to reveal additional insights into pts' response to study treatments or characteristics of the disease in later lines of therapy... Adults with CML-CP previously treated with ≥2 TKIs with intolerance of their last TKI or lack of efficacy per 2013 European LeukemiaNet recommendations and without BCR::ABL1 T315I or V299L mutations were randomized 2:1 to ASC 40 mg twice daily or BOS 500 mg once daily... ASXL1 mutations are most frequently detected at CML diagnosis and were enriched at BL in this study of pts with CML-CP previously treated with ≥2 TKIs, which is consistent with a role in TKI resistance. RUNX1 and IKZF1 mutations, which are associated with progression to accelerated or blast phase in CML, were very rare in this pt population, supporting their role in CML disease progression. The high frequency of co-occurrence of BCR::ABL1 mutations and blood cancer gene mutations in CML-CP is an important finding since cancer gene mutations could modify response to TKIs in individual pts.

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

IL-33-ST2 signaling promoted the resistance of CML cells to the tyrosine kinase inhibitor (TKI) nilotinib and of AML cells to standard chemotherapy. Thus, inhibiting IL-33-ST2 signaling may target LSCs to overcome resistance to chemotherapy or TKIs in these subtypes of leukemia.

The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

In summary, the current meta-analysis highlights the frequency of IKZF1 deletion and its negative impact on survival in childhood ALL. Further studies exploring the influence of IKZF1 deletion in the presence of classical cytogenetic and other copy number alterations would further help in characterising its prognostic role.

With this practical approach, we reported a high incidence of BCR::ABL1-like ALLs, and a lower frequency of CRLF2 alteration & associated CGFs. Recognising this entity, early at diagnosis is crucial to optimise personalised treatment strategies.

The study comprised samples from patients enrolled in the phase II GIMEMA LAL2116 chemotherapy-free protocol for newly diagnosed adult Ph+ ALL and based on the administration of the second generation TKI dasatinib followed by the bispecific monoclonal antibody blinatumomab 2 . The ddPCR proved as reliable and accurate as SS to detect the T315I BCR::ABL1 KD mutation. Furthermore, the ddPCR proved to be more sensitive for predict molecular relapse before the increase in MRD where, in some cases, the SS failed to detect the T315I mutation. Further efforts are ongoing to expandthis screening also to other ABL1 mutations, considering the always more frequent use of ponatinib in the first-line setting.

With novel gene fusions and uncovered associations between the dynamics of MRD decline, TP53 and RUNX1 high burden mutations in this real-world cohort, our dataset provides valuable, clinically relevant insights to the genomic and transcriptomic landscape of children diagnosed with ALL. Pediatric, ALL, Prognosis, Mutation analysis

Aims: This work of the Czech Leukemia Study Group for Life is focused on 79 adult B-ALL patients treated with GMALL 07/2003 protocol (and with imatinib in Ph+ ALL)... IKZF1 alterations were more frequent in Ph+ ALL. Their detection correlated with shorter OS in both Ph+ and Ph- ALL adults treated with GMALL 07/2003 protocol. Individuals with IKZF plus had the worse outcome.

PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1-/- cells when compared to the Abl1 + /+ counterparts...Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors.

We identified the role of Atp8a1 on hematopoiesis and HSCs. Atp8a1 deletion resulted in the loss of phosphatidylserine asymmetry and intracellular signal transduction chaos.

OGM assays were more comprehensive, and novel rare SVs were identified in ALL. Combining the results of gene fusions between different technologies will provide more accurate predictions for ALL classifications. The combination of aberrant SVs may synergize to influence the efficacy of imatinib, which warrants further investigations.

Later, he was given Dashatinib combined with Venetoclax, Ponatinib combined with Venetoclax,Blinatumomab, chemotherapy, CD19-CART, CD22-CART, and the disease didn't control...After chemotherapy with imatinib, the BM reached immunologic remission, and the quantitative fusion gene was continuously positive. During the period, TKI was adjusted to dasatinib and nilotinib, and the treatment was not continued due to intolerance...Flumatinib combined with chemotherapy and olverembatinib combined with chemotherapy were ineffective...After admission to our hospital, azacytidine was given in combination with VP, Venetoclax and olverembatinib... Adult relapses are difficult to treat Ph+ALL, and the chemotherapy effect is very poor, especially in elderly patients, and the tolerance to chemotherapy is also very poor. Immune targeted therapy brings new hope. The combination of Ino.

Thus, early distinguishing of the two subtypes is essential to enable optimal treatment approach and therapy adjustments in upcoming trials. For the typical Ph+ ALL, TKI and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, representing one-fourth to one-third of childhood patients diagnosed as BCR::ABL1-positive ALL, no relevant risk factor applicable for therapy tailoring was found so far.

The GIMEMA LAL2317 is a clinical trial designed for newly diagnosed adult B-lineage Ph-negative ALL that includes two cycles of blinatumomab in the consolidation phase...1. Chiaretti S et al., BJH 2018

This prospective study in a real-world setting 1) demonstrated the diagnostic power of WGTS with an accuracy comparable to gold standard techniques, 2) added important prognostic information, 3) identified potential new therapeutic targets and 4) gave new insights into disease biology. WGTS significantly will improve and refine diagnostics in the future.

The 2G-TKI patients were enrolled in either DIRECT; CML12 (n=72), where patients commenced dasatinib 100mg daily before dose modification, or either ENESTxtnd or PINNACLE; CML11 (n=44) where patients commenced nilotinib 300mg twice daily. The effect for imatinib treated patients was evident despite a starting dose of 600mg and more stringent treatment intervention than currently recommended. This supports a strategy of mutation analysis at diagnosis of CP-CML for optimal TKI selection.

The implementation of this NGS assay allows for a comprehensive evaluation of the mutational spectrum of myeloid malignancies in Lebanese patients. The detection of these actionable gene mutations contributes to an early diagnosis, appropriate individualized treatment, enhanced prediction of target therapy response, and improved clinical outcome.

Hsp27 combined with CD73, CD58, CD24, and backbone markers allows monitoring MRD in virtually all patients with BCP-ALL.

P1, N=92, Recruiting, Andrew E. Place | Not yet recruiting --> Recruiting

These results indicated that BCR/ABL1Δexon7-8-9 showed poorer sensitivity to imatinib and nilotinib than wild-type BCR/ABL1. It enriched the mechanism of spliceosome involved in TKIs resistance. Monitoring the expression of BCR/ABL1?E7-8-9 helps guide the treatment of CML patients in the clinic.

In adult patients, ABL1 CNA emerged as an independent indicator of poor prognosis. The observed molecular heterogeneity in T-ALL may provide the basis for variations observed in clinical response in T-ALL and MLPA based CNA detection may help in risk stratification of these patients.

MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.

In our cohort, patients with TCR rearrangements had an excellent prognosis regardless of the presence of other aberrations. Although data on larger series are clearly required, w e suppose, that these children could benefit from less-intensive therapy because they may experience fewer therapeutic consequences of toxic treatment.

P1, N=92, Not yet recruiting, Andrew E. Place

Dasatinib was administered with the temporal use of hydroxyurea and VP-16, which resulted in rapid disappearance of her intrapelvic mass and complete hematologic response within 1 month. Furthermore, in our case, a mutational analysis at diagnosis revealed an in-frame exon 4 deletion in ABL1, which is reported to decrease cell proliferation. This fact is intriguing because her clinical outcome was relatively favorable.

Ph-like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.

OGM was able to confirm and accurately detect structural variations that included duplications, deletions, translocations, insertions, copy number variations, and mosaicism. OGM defined the breakpoints and translocation partners ambiguous by karyotyping. We anticipate that this approach of obtaining high-resolution genomic data at reduced cost will facilitate more precise diagnoses and better prognostication of malignancies not previously possible.

ETV6-RUNX1 and BCR-ABL1 are recurrent primary events in pediatric B-cell precursor acute lymphoblastic leukemia (B-ALL), being the former the most common one. Elegant studies have shown that these are founder events, but additional genetic events are needed for leukemia development. Nonetheless, these common primary alterations are typically mutually exclusive. The presence of both ETV6-RUNX1 and BCR-ABL1 is a very rare event which has been previously reported in only two B-ALL cases, being one pediatric and one adult patient. Herein, we report a rare pediatric B-ALL case with simultaneous occurrence of ETV6-RUNX1 and BCR-ABL1 . The 5-year-old boy was admitted to Hospital Federal da Lagoa, Rio de Janeiro, Brazil. At clinical investigation, he presented hepatosplenomegaly, a white blood cell count of 0.7×109/L, 94% of blasts, Hb of 6.5 g/L, and platelet count of 16×109/L. The patient was treated according to the AIEOP-BFM protocol. He presented a poor prednisone response (at day 8; >1000 circulating lymphoblasts), the minimal residual disease at day 33 was negative (0.08%), and he was considered in complete remission. Four months after the diagnosis, the child is alive with negative levels of residual disease. The immunophenotyping was characterized by nTdT (low), CD10, CD13, CD19, CD21, CD22, CD24, CD33, CD34, CD38 and CD45, cCD66c, cCD79, CD81, CD123, and CD58 positive cells in 94.1% of lymphoblast cells and a diploid profile (DNA index of 1.09). ETV6-RUNX1 and BCR-ABL1 p210 were identified by reverse transcriptase PCR (RT-PCR). The presence of both rearrangements was confirmed by sanger sequencing. Moreover, additional copy number (CNA) were evaluated by multiplex ligation-dependent probe amplification (MLPA) using SALSA MLPA P335-C1. Deletions affecting IKZF1 (exons 2 and 3), CDKN2A (exons 2 and 5), CDKN2B (exon 2), PAX5 (exon 1), and ETV6 (exons 2, 3, 5 and 8) were detected. In consonance with previous studies, these CNAs are the most frequently secondary events found in patients with ETV6-RUNX1 . Of note, IKZF1 deletions are enriched in patients with BCR-ABL1. Due to the lack of material for FISH analysis, the clonality of both biomarkers could not be verified. However, we observed a low load of BCR-ABL1 p210 transcript in comparison with the endogenous gene, suggesting that this fusion gene could be present in subclones. In Conclusion , to the best of our knowledge, this is the second pediatric case identified with ETV6-RUNX1 and BCR-ABL1 gene rearrangement in concomitance, but is the first case reported with the p210 transcript, which is extremely rare in B-ALL. Previous studies have shown that the additional genetic events found can impact the usually favorable prognosis of ETV6-RUNX1 – positive B-ALL. The clinical significance for these rare patients with both rearrangements remains unclear due to the small number of reported cases to date. Therefore, it is very important to describe more cases which will ultimately enable future studies with larger series and clarify this enigmatic subgroup.