Philadelphia Chromosome–like Acute Lymphoblastic Leukemia

Pui, Ching‐Hon; Roberts, Kathryn G.; Yang, Jun J.; Mullighan, Charles G.

doi:10.1016/j.clml.2017.03.299

Cited by 104 publications

(101 citation statements)

References 38 publications

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“…Leukemia developed only in one CB out of 13 batches of CB that were transduced with IL7RAins vector. Recent gene wide association (GWAS) studies have described several germline single nucleotide polymorphic (SNP) alleles thought to predispose to BCP-ALL [43][44][45][46][47][48][49][50][51][52] .…”

Section: Initiation Of De-novo Leukemia After Serial Transplantation mentioning

confidence: 99%

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Geron

Savino

Tal

et al. 2020

Preprint

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent preleukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphialike (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown. IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development. Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγ null mice resulted in B-cell differentiation arrest with aberrant expression of CD34 + and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34 + CD10 high CD19 low immunophenotype. The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Phlike BCP-ALL development from normal human hematopoietic progenitors in vivo.

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Section: Initiation Of De-novo Leukemia After Serial Transplantation mentioning

confidence: 99%

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Geron

Savino

Tal

et al. 2020

Preprint

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“…Ph-like ALL can be detected in approximately: 10%-15% of children, 20%-25% of adolescents and 20%-23% of adults with B-cell ALL [88,[90][91][92]. It is encountered more frequently in male adults and has associations with: Hispanic ethnicity, Down's syndrome and inherited genetic variants in GATA3 (rs3824662) [91,92].…”

Section: Philadelphia Chromosome-like Allmentioning

confidence: 99%

“…It is encountered more frequently in male adults and has associations with: Hispanic ethnicity, Down's syndrome and inherited genetic variants in GATA3 (rs3824662) [91,92]. When compared to other pre-B ALL subtypes, Ph-like ALL has the following characteristic features: (1) higher median leukocyte count at presentation, (2) higher median levels of MRD at the end of induction therapy, (3) inferior estimated event-free survival (EFS) at 5 years [58% versus (vs.) 84% in children, 41% vs. 83% in adolescents and 24% vs 63% in young adults], and (4) inferior estimated OS at 5 years [73% vs. 92% in children, 66% vs. 93% in adolescents and 26% vs 75% in young adults [88].…”

Section: Philadelphia Chromosome-like Allmentioning

confidence: 99%

“…Thus, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents a unique opportunity for harnessing international collaboration to further improve the outcome of ALL patients in general [92]. Therefore, prospective studies are needed to determine if incorporation of TKIs targeting kinase alterations into the intensive chemotherapeutic regimens will improve the outcome of patients with Ph-like ALL [91]. However, in a group of patients with B-cell ALL treated with frontline hyper-CVAD-based chemotherapy, the outcome of Ph-like ALL was inferior to the other B-cell ALL subgroups [90].…”

Section: Page 8 Of 15mentioning

confidence: 99%

“…Although most patients with Ph-like ALL have MRD after induction chemotherapy and poor EFS, approximately 40% of pediatric patients with Ph-like ALL respond well to chemotherapy and can be cured with relatively low-intensity therapies [91]. Nevertheless, novel therapies are needed to improve the outcome of patients with Ph-like ALL as this this subtype of ALL represents a disease where precision medicine testing, and treatment approach should be implemented [90,94,99].…”

Section: Page 8 Of 15mentioning

confidence: 99%

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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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Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia

2018

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Therapies targeting specific transcripts or leukemic cell surface antigens are major breakthroughs in the treatment of adults with ALL. The incorporation of new monoclonal antibodies and other targeted approaches into frontline regimens is showing promising results. If confirmed, such strategies may increase the cure rates in adults to levels achieved in pediatric ALL and reduce the need for intensive and prolonged chemotherapy.

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Philadelphia Chromosome–like Acute Lymphoblastic Leukemia

Cited by 104 publications

References 38 publications

An instructive role for IL7RA in the development of human B-cell precursor leukemia

An instructive role for IL7RA in the development of human B-cell precursor leukemia

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

Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia

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