The role of constitutive activation of FMS-related tyrosine kinase-3 and
            <i>NRas/KRas</i>
            mutational status in infants with
            <i>KMT2A</i>
            -rearranged acute lymphoblastic leukemia

Fedders, Henning; Alsadeq, Ameera; Schmäh, Juliane; Vogiatzi, Fotini; Zimmermann, Martin; Möricke, Anja; Lenk, Lennart; Stadt, Udo zur; Horstmann, Martin; Pieters, Rob; Schrappe, Martin; Stanulla, Martin; Cario, Gunnar; Schewe, Denis

doi:10.3324/haematol.2017.169870

Cited by 12 publications

(7 citation statements)

References 14 publications

(8 reference statements)

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“…The CNS is involved in about 5% of MLLr BCP-ALL patients [66]. MLLr-ALL have frequent mutations in the RAS pathway [67][68][69], which as previously discussed was shown to be linked with an increased risk of CNS infiltration [44]. Furthermore, KRAS activation was shown to promote CNS infiltration of MLLr cells harboring the MLL-AF4 fusion gene [70].…”

Section: The Relevance Of Cytogeneticsmentioning

confidence: 82%

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Lenk

Alsadeq

Schewe

2020

Cancer Metastasis Rev

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. We also focus on the impact of ALL cytogenetic subtypes on features associated with a particular CNS tropism. Finally, we speculate on new perspectives in the treatment of ALL in the CNS, including ideas on the impact of novel immunotherapies.

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Section: The Relevance Of Cytogeneticsmentioning

confidence: 82%

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Lenk

Alsadeq

Schewe

2020

Cancer Metastasis Rev

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“…The mutational landscape of KMT2A r acute leukemia is well‐characterized overall. Of particular interest, variants within the PI3K‐RAS pathway have been identified in cases of KMT2A‐MLLT10 AML and B‐ALL across all age groups 55‐57 . One study also observed that inactivating mutations of PAX5 were more frequently associated with pediatric cases bearing KMT2A‐MLLT10 and KMT2A‐MLLT3 , compared with other KMT2A r 55 .…”

Section: Prognosis In Allmentioning

confidence: 99%

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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Rearrangements of the MLLT10 gene occur in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), most commonly T-lineage ALL (T-ALL), in patients of all ages. MLLT10 rearranged (MLLT10r) acute leukemia presents a complex diagnostic and therapeutic challenge due to frequent presentation of immature or mixed phenotype, and a lack of consensus regarding optimal therapy. Cases of MLLT10r AML or TALL bearing immature phenotype are at high risk of poor outcome, but the underlying molecular mechanisms and sensitivity to targeted therapies remain poorly characterized. This review addresses the incidence and prognostic significance of MLLT10r in acute leukemia, and how the aberrant gene expression profile of this disease can inform potential targeted therapeutic strategies. Understanding the underlying genomics of MLLT10r acute leukemia, both clinically and molecularly, will improve prognostic stratification and accelerate the development of targeted therapeutic strategies, to improve patient outcomes.

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“…When activated by mutations, KRAS protein activates downstream cytosolic effectors including the RAF/MEK/ERK pathway and the PI3K/AKT/mTOR pathway to promote cell growth, proliferation, and survival 9 , 10 . The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma 11 , colorectal cancer 12 , pancreatic cancer 13 , and leukemias 14 .…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic characteristics and survival outcome in patients with advanced lung adenocarcinoma and KRAS mutation

Yang

Fan

et al. 2018

J. Cancer

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Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are one of the most common observed genetic events in lung adenocarcinoma. The present study aimed to characterize treatment patterns and to estimate survival for patients in China with advanced lung adenocarcinoma and KRAS mutation. We identified KRAS-mutant lung adenocarcinoma between February 2013 and June 2017 in Zhejiang Cancer Hospital. Patients' characteristics and treatment outcomes were analyzed. A total of 159 lung adenocarcinoma were included, and 26 (16.4%) patients harbored KRAS mutations. Compared to KRAS-wild patients, patients with KRAS-mutant tumors were more likely to be smokers (76.9% vs. 51.9%, P = 0.029). Median tumor mutation burden (TMB) was significantly higher in the KRAS-mutant cohort than in the KRAS-wild cohort (5.4 vs. 4.2 mutations/megabases; P=0.041). Of the 93 patients receiving first-line chemotherapy, the median progression-free survival (PFS) in the KRAS-mutant group was significantly shorter than in the KRAS-wild group (1.5 vs. 7.2 months; P<0.001). The median overall survival (OS) in the KRAS-mutant group was also significantly shorter than in the KRAS-wild group (hazard ratio for progression or death for patients with KRAS mutation, 3.260; 95% CI, 1.516 to 7.013; P=0.001). In summary, our findings have several important implications for the molecular characterization and therapeutic outcome of lung adenocarcinoma initiated by oncogenic KRAS. Since the number of KRAS-mutant lung cancer is considerable, it should be taken seriously in clinical diagnosis and treatment. KRAS-mutant lung adenocarcinoma was not sensitive to chemotherapy, new and effective drugs targeting the KRAS pathway are in urgent need.

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The role of constitutive activation of FMS-related tyrosine kinase-3 and NRas/KRas mutational status in infants with KMT2A -rearranged acute lymphoblastic leukemia

Abstract: Constitutive activation of the FMS-related tyrosine kinase-3 (FLT3) by mutations or high expression levels is common in acute leukemias.1 Aberrant FLT3 signaling is mediated via the RAS/MAPK and PI-3-Kinase/AKT pathways leading to proliferation, survival, and therapy resistance.

Cited by 12 publications

References 14 publications

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Clinicopathologic characteristics and survival outcome in patients with advanced lung adenocarcinoma and KRAS mutation

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