Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia

Ernst, Thomas; Busch, Melinda; Rinke, Jenny; Ernst, Jochen; Haferlach, Claudia; Beck, James F.; Hochhaus, Andreas; Gruhn, Bernd

doi:10.1038/s41375-018-0157-2

Cited by 40 publications

(28 citation statements)

References 15 publications

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“…The high-mutation frequency of ASXL1 has been described previously. 17,18,[44][45][46] Mutations in other epigenetic modifiers were also found and associated with unfavorable outcome, as recently reported. 19,47,48 AP/BP and CP cases with unfavorable response also harbored mutations in PTPR genes, which are tumor suppressors 49 and negative regulators of JAK/STAT signaling.…”

Section: Discussionsupporting

confidence: 73%

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Awad

Kankainen

Ojala³

et al. 2020

Blood Advances

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

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Section: Discussionsupporting

confidence: 73%

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Awad

Kankainen

Ojala³

et al. 2020

Blood Advances

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“…1,3 Children and adolescents with CML tend to present with more aggressive features (higher white blood cell count, larger spleen size in proportion to body size, higher frequency of advanced phases at diagnosis) 1,4 ; show a distribution of BCR-ABL1 breakpoints resembling Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) 5 ; and have a higher proportion of mutated cancer driver genes. 6,7 Risk scores that are wellestablished in adults for predicting outcomes [8][9][10] (eg, Sokal, EURO, European Treatment and Outcome Study, and European Treatment and Outcome Study long-term survival score) do not apply in children, 11 with the exception of European Treatment and Outcome Study long-term survival, which may predict progression-free survival but not overall survival (OS). 12 The advent of tyrosine kinase inhibitors (TKIs) in the past 2 decades has changed the landscape of CML treatment dramatically, with life expectancy in adult patients now almost identical to that of the agematched healthy population.…”

Section: Introductionmentioning

confidence: 99%

How I treat chronic myeloid leukemia in children and adolescents

Hijiya

Suttorp

2019

Blood

112

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Evidence-based recommendations have been established for treatment of chronic myeloid leukemia (CML) in adults treated with tyrosine kinase inhibitors (TKIs), but the rarity of this leukemia in children and adolescents makes it challenging to develop similar recommendations in pediatrics. In addition to imatinib, which was approved for pediatric CML in 2003, the second-generation TKIs dasatinib and nilotinib were recently approved for use in children, expanding the therapeutic options and pushing allogeneic stem cell transplantation to a third-line treatment of most pediatric cases. Yet, without sufficient data on efficacy and safety specific to pediatric patients, the selection of a TKI continues to rely on clinical experience in adults. Here, we present 4 case scenarios highlighting common yet challenging issues encountered in the treatment of pediatric CML (suboptimal response, poor treatment adherence, growth retardation, and presentation in advanced phases). Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are additional significant obstacles that require further clinical investigation through international collaboration.

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“…This was followed by a descriptive literature review of original studies and expert opinion manuscripts evaluating management and outcome of CML in children and adolescents. In addition, published guidelines, guidance documents, and standard of care documents for the management of adults with CML were reviewed . The data gathered were presented and reviewed within the COG CML Working Group.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, published guidelines, guidance documents, and standard of care documents for the management of adults with CML were reviewed. 1,2,[4][5][6][7][8][9][10][11][14][15][16][17][18][19][20][21] The data gathered were presented and reviewed within the COG CML Working Group. Based on the review, recommendations were developed.…”

Section: Methodsmentioning

confidence: 99%

“…However, children, adolescents, and young adults tend to have more aggressive clinical presentation than that in adults . Recent data indicate that some genetic differences exist in pediatric CML compared to adult disease; for example, 60% of pediatric patients have ASXL1 mutation compared to only 15% of adults . Further, children with CML are exposed to their disease and its therapy during periods of growth and development—and life‐long treatment is required in most cases—for a much longer period of time compared to those who are diagnosed at a much later age, assuming that most patients require life‐long therapy.…”

Section: Introductionmentioning

confidence: 99%

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Management of chronic myeloid leukemia in children and adolescents: Recommendations from the Children's Oncology Group CML Working Group

Athale

Hijiya

Patterson

et al. 2019

Pediatric Blood & Cancer

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Chronic myeloid leukemia (CML) accounts for 2‐3% of leukemias in children under 15 and 9% in adolescents aged 15‐19. The diagnosis and management of CML in children, adolescents, and young adults have several differences compared to that in adults. This review outlines the diagnosis and management of the underlying disease as well as challenges that can occur when dealing with CML in this patient population.

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Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia

Cited by 40 publications

References 15 publications

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

How I treat chronic myeloid leukemia in children and adolescents

Management of chronic myeloid leukemia in children and adolescents: Recommendations from the Children's Oncology Group CML Working Group

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