The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Shiraz, Parveen; Payne, Kimberly J.; Muffly, Lori

doi:10.3390/ijms21062193

Cited by 35 publications

(37 citation statements)

References 93 publications

(173 reference statements)

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“…Since kinase-activating alterations were identified in over 90% of pediatric Ph-like ALL [24], and most of them converge on clinically actionable signaling, there is a great interest in identifying Ph-like patients, aiming to improve their outcome by using TK inhibitors (TKi) and JAK inhibitors. Different preclinical studies supported the evaluation of TKI Imatinib or Dasatinib in combination with chemotherapy [33] and several case reports corroborate the efficacy of TKIs in refractory Ph-like ALL patients with PDGFRB fusions [34][35][36][37]. For that reason, Dasatinib is currently tested in combination with chemotherapy to improve the cure rate of pediatric patients (NCT03117751; NCT01406756).…”

Section: Ph-like B-allmentioning

confidence: 99%

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

Ratti

Lonetti

Follo

et al. 2020

Cancers

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B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes.

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Section: Ph-like B-allmentioning

confidence: 99%

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

Ratti

Lonetti

Follo

et al. 2020

Cancers

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“…Similar to other Ph-like ALL subtypes, JAK2 r often co-occur with deletions in genes involved in B-cell development including IKZF1 (IKAROS family zinc finger 1) ( Mullighan et al, 2008 ; Mullighan et al, 2009b ). The most common IKZF1 alteration associated with Ph-like (and JAK2 r) ALL is a deletion of IKZF1 exons 3-6, encoding the dominant negative IK6 isoform of IKAROS, which lacks the N-terminal DNA binding domain ( Roberts et al, 2014a ; Tran et al, 2018 ; Shiraz et al, 2020 ). IKAROS IK6 is unable to bind DNA to regulate the expression of genes required for B-cell differentiation, implying that JAK2 r and IKZF1 deletions both drive deregulation of B-cell maturation and promote development of B-ALL ( Mullighan et al, 2009b ; Harvey et al, 2010 ; Pui et al, 2017 ).…”

Section: Jak2 Rearrangements In Ph-like Allmentioning

confidence: 99%

JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies

Downes

McClure

McDougal

et al. 2022

Front. Cell Dev. Biol.

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.

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“…The vast majority of Ph-like ALL patients represent a poor outcome, with the five-year EFS amounting to about 41%, and patients mostly harboring a positive MRD status after the end of induction, despite conventional chemotherapy [ 27 ]. Ph-like ALL is characterized by a spectrum of genetic alterations activating tyrosine kinase (ABL class fusions and involving other rare kinases: NTKR3, BLNK, DGKH, PTK2B, FLT3, FGFR1, and TYK2), cytokine receptor genes (JAK-STAT signaling pathways), and sequence mutations (FLT3, IL7R, and SH2B3 are the most common) [ 27 , 42 , 43 ]. Among the other half of pediatric Ph-like ALL subgroups without CRLF2 rearrangement, 15–20% harbored ABL-class gene fusions including ABL1, ABL2, PDGFRA, PDGFRB, LYN, and CSF1R lesions, which are potential targets for an ABL-class first-generation tyrosine kinase inhibitor—imatinib—or a second-generation multikinase ABL1/SRC inhibitor—dasatinib [ 27 , 44 , 45 , 46 ].…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

Lejman

Kuśmierczuk

Bednarz

et al. 2021

IJMS

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Targeted therapy has revolutionized the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) with specific genetic abnormalities. It is still being described as a new landmark therapeutic approach. The main purpose of the use of molecularly targeted drugs and immunotherapy in the treatment of ALL is to improve the treatment outcomes and reduce the doses of conventional chemotherapy, while maintaining the effectiveness of the therapy. Despite promising treatment results, there is limited clinical research on the effect of target cell therapy on the potential toxic events in children and adolescents. The recent development of highly specific molecular methods has led to an improvement in the identification of numerous unique expression profiles of acute lymphoblastic leukemia. The detection of specific genetic mutations determines patients’ risk groups, which allows for patient stratification and for an adjustment of the directed and personalized target therapies that are focused on particular molecular alteration. This review summarizes the knowledge concerning the toxicity of molecular-targeted drugs and immunotherapies applied in childhood ALL.

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The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Cited by 35 publications

References 93 publications

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

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