Childhood acute lymphoblastic leukemia: Integrating genomics into therapy

Tasian, Sarah K.; Loh, Mignon L.; Hunger, Stephen P.

doi:10.1002/cncr.29573

Cited by 63 publications

(76 citation statements)

References 139 publications

(337 reference statements)

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“…Point mutations in the JAK kinases are usually accompanied by rearrangements of CRLF2, whereas IL7R mutations arise mostly within the transmembrane domain to promote constitutive JAK-STAT signaling. Ras pathway mutations occur in 4% of patients with Ph-like ALL; these include activating mutations of NRAS, KRAS, PTPN11, and NF1, which have also been reported in other ALL subtypes such as hypodiploid ALL, 25 KMT2A-rearranged ALL, 26 and relapsed ALL. 26 Rare kinase fusions involving NTRK3 and DGKH occur in 0.9% of Ph-like ALL.…”

Section: Ph-like All: the Genomic Landscapementioning

confidence: 97%

Ph-like acute lymphoblastic leukemia

Tran

Loh

2016

Hematology

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Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute–defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.

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Section: Ph-like All: the Genomic Landscapementioning

confidence: 97%

Ph-like acute lymphoblastic leukemia

Tran

Loh

2016

Hematology

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“…The types of gene rearrangements that are seen in patients with T-cell ALL, their subtypes as well as examples of each subtypes are shown in Table 5 [63]. The signaling pathways as well as the various genetic mutations that are found in patients with B-cell ALL and T-cell type of ALL are shown in Tables 6 and 7 respectively [63][64][65][66][67][68][69].…”

Section: Molecular and Cytogenetic Abnormalities In All Patientsmentioning

confidence: 99%

“…Examples of the main molecular markers and genetic targets in ALL are: BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1, IKZF1, CDKN2A, CDKN2B and NOTCH1 [123]. A detailed list of genetic abnormalities and molecular markers that have been found in patients with ALL are included in Tables 4-7 [33,58,59,[63][64][65][66][67][68][69]. Examples of main novel and targeted therapies that are currently used in the treatment of ALL are: rituximab, nelarabine, TKIs, blinatumomab and CAR-T cells [123].…”

Section: Recent Therapeutic Modalitiesmentioning

confidence: 99%

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

Wk¹,

Dridi²,

Ka³

2017

J Mol Genet Med

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The recent improvements in the outcomes of patients with acute lymphoblastic leukemia reflect the progress in the field of diagnostics and the achievements in therapeutic interventions. In particular, the availability of more advanced technology in the cytogenetic and molecular laboratories has resulted in the stratification of patients into specific risk groups and thus several novel agents as well as targeted therapies have been introduced. Additionally, precision medicine will be applicable in the near future and thus the recent developments will facilitate the provision of safer modalities of therapy that may ultimately yield not only higher responses but also improved survival rates.This review represents a recent update on the role of various cytogenetic assays and molecular techniques in patients with acute lymphoblastic leukemia. It is composed of a number of sections including: history of cytogenetics, disease etiology and pathophysiology, utilization of various cytogenetic assays diagnostically, disease-specific cytogenetic and molecular abnormalities, common disease genetic subtypes, prognosis and risk stratification, refractory and relapsed disease, novel therapies, precision medicine and drug repurposing.

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“…Such approaches are very well developed in cancer medicine with several examples of successful precision medicine applications in breast, prostate, ovarian, colon and pancreatic cancer [1][2][3][4][5][6] and this list is by no means complete. Cardiovascular medicine in general and hypertension in particular both lag behind oncology in this respect.…”

mentioning

confidence: 99%

“…The contribution of each individual SNP was approximately 1 mmHg for systolic and 0.5 mmHg for diastolic BP 12 . The weighted genetic risk scores (GRS), 4 which were calculated for all 29 SNPs, showed highly significant associations with coronary heart disease, left ventricular hypertrophy and stroke but not with markers of renal function 12 . The quality and the breadth of phenotyping in these very large, multi-centre studies is not perfect, with the limited number of BP and other phenotypes used 14 .…”

mentioning

confidence: 99%