Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

Ma, Xiaotu; Edmonson, Michael N.; Yergeau, Donald; Muzny, Donna M.; Hampton, Oliver A.; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C.; Wheeler, David A.; Ma, Jing; Doddapaneni, Harshavardhan; Vadodaria, Bhavin; Wu, Gang; Nagahawatte, Panduka; Carroll, William L.; Chen, I‐Ming; Gastier‐Foster, Julie M.; Relling, Mary V.; Smith, Malcolm A.; Devidas, Meenakshi; Auvil, Jaime M. Guidry; Downing, James R.; Loh, Mignon L.; Willman, Cheryl L.; Gerhard, Daniela S.; Mullighan, Charles G.; Hunger, Stephen P.; Zhang, Jinghui

doi:10.1038/ncomms7604

Cited by 302 publications

(380 citation statements)

References 25 publications

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“…Relapse reflects two cooperating processes: the primary leukemogenic process driving the growth and survival of leukemic cells and the selection pressure imposed by frontline therapy. Similar to other studies of relapsed ALL (21,25,26,44,50,59), we observed increased RAS activation in relapse. Indeed, it has been proposed that RAS may mediate resistance to chemotherapy.…”

Section: Discussionsupporting

confidence: 80%

“…Intriguingly, however, we have found no NT5C2 mutations in our cohort. Previous studies identified NT5C2 mutations in 8-45% of the relapses of BCPALLs (34,35,44). Mutations in NT5C2 were associated with early relapses, whereas in our cohort the median time to relapse was relatively long, 1,071 d (range 375-2,226 d).…”

Section: Discussioncontrasting

confidence: 39%

“…The relapse-enriched mutations found in our DS-ALL cohort are similar to those found in other ALL subtypes (21,25,26,30,44,50,59). Intriguingly, however, we have found no NT5C2 mutations in our cohort.…”

Section: Discussionmentioning

confidence: 42%

“…To further validate these findings, we explored publicly available data. Additional mutations identified in USP9X in several studies (25,(41)(42)(43)(44) are depicted in Fig. 4B.…”

Section: Temporal Association Of Somatic Mutations Between Diagnosis Andmentioning

confidence: 99%

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Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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Section: Discussionsupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 39%

Section: Discussionmentioning

confidence: 42%

“…To further validate these findings, we explored publicly available data. Additional mutations identified in USP9X in several studies (25,(41)(42)(43)(44) are depicted in Fig. 4B.…”

Section: Temporal Association Of Somatic Mutations Between Diagnosis Andmentioning

confidence: 99%

See 2 more Smart Citations

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Ma and colleagues confirmed the frequent mutation of NT5C2 in relapsed B-ALL and identified additional signaling pathways that are frequently mutated, including CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1. 8 While we have a comprehensive picture of the genomic complexity of T-ALL at diagnosis, 9-12 data on relapsed T-ALL cases are limited. In this issue of Haematologica, Kunz and colleagues explore the genetic basis and clonal evolution of diagnosis and relapse samples in pediatric T-ALL.…”

confidence: 99%

The origin of relapse in pediatric T-cell acute lymphoblastic leukemia

Vicente¹,

Cools²

2015

Haematologica

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Improving Patient Outcomes With Cancer Genomics

Schnepp

Bosse

Maris

2015

JAMA

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Precision medicine, the individualization of health care based on unique patient-specific variables, is not new, especially within oncology. Historically, there has been a "depersonalization" of cancer care by defining histotype-specific standard-of-care treatments for the majority of malignancies, although in contrast oncologists have been adept at individualizing therapy, especially when confronted with disease relapse. Practicing oncologists seek evidence-based approaches to improve patient outcomes, but much of the current personalization of care remains largely empirical. Nevertheless, over the past decade there has been increasing enthusiasm for using genomic data to more precisely diagnose cancer, predict outcomes, and prescribe "targeted" therapies. Although substantial progress has been made, both anticipated and unanticipated barriers exist in integrating sequencing technologies into the care of patients with cancer. Clearly, for multiple reasons, many challenges remain to prove that personalized genomic medicine can substantively improve outcomes for patients with cancer. These challenges are further accentuated with childhood cancers.

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Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

Cited by 302 publications

References 25 publications

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

The origin of relapse in pediatric T-cell acute lymphoblastic leukemia

Improving Patient Outcomes With Cancer Genomics

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