The genomic landscape of hypodiploid acute lymphoblastic leukemia

Authors

Holmfeldt L

Wei L

Diaz-Flores E

Walsh M

Zhang J

Ding L

Payne-Turner D

Churchman M

Andersson A

Chen SC

McCastlain K

Becksfort J

Ma J

Wu G

Patel SN

Heatley SL

Phillips LA

Song G

Easton J

Parker M

Chen X

Ruber M

Boggs K

Vadodaria B

Hedlund E

Drenberg C

Baker S

Pei D

Cheng C

Huber R

Mullighan CG

Doi

10.1038/ng.2532

PMID: 23334668 · DOI: 10.1038/ng.2532 · Journal: Nature Genetics (2013)

TL;DR

This study performed the first comprehensive genomic characterization of hypodiploid acute lymphoblastic leukemia (ALL) in 124 pediatric cases using whole-genome/exome sequencing and SNP microarray profiling. It identified two genetically distinct subtypes: near haploid ALL (24-31 chromosomes) driven by RTK/Ras pathway alterations (71%) and IKZF3 deletions (13%), and low hypodiploid ALL (32-39 chromosomes) characterized by TP53 mutations (91.2%), IKZF2 deletions (53%), and RB1 alterations (41%). Nearly half of TP53 mutations in pediatric low hypodiploid ALL were inherited, linking this subtype to Li-Fraumeni syndrome. Both subtypes showed activation of Ras and PI3K signaling and sensitivity to PI3K inhibitors ex vivo.

Cohort & data

  • 124 pediatric hypodiploid ALL cases (50 near haploid, 26 low hypodiploid, 18 masked hypodiploid, 22 near diploid) plus 8 masked low hypodiploid; matched remission DNA for 89 cases.
  • Additional adult ALL cohort of 117 cases including 11 low hypodiploid cases.
  • Whole-genome sequencing of 20 cases (11 near haploid, 9 low hypodiploid) and whole-exome sequencing of 20 cases (14 near haploid, 6 low hypodiploid).
  • Genome-wide copy number profiling using Affymetrix SNP 6.0 microarrays.
  • Gene expression profiling using Affymetrix U133 Plus 2.0 microarrays.
  • Sanger sequencing of selected exons in 8 genes and all coding exons in 11 genes across the full cohort.
  • Dataset: all_stjude_2013; dbGaP accession phs000341.v1.p1.

Key findings

  • Near haploid ALL (24-31 chromosomes) harbors RTK/Ras signaling alterations in 70.6% of cases, including NF1 (44.1%), NRAS, KRAS, FLT3, PTPN11, and MAPK1 mutations/deletions.
  • A novel intragenic NF1 deletion (exons 15-35) was identified in 17/21 NF1-deleted near haploid cases, resulting in loss of the GAP domain via aberrant RAG activity.
  • Low hypodiploid ALL (32-39 chromosomes) has TP53 alterations in 91.2% of pediatric cases and 90.9% of adult cases (P = 1.65 x 10^-20 vs non-low hypodiploid B-ALL).
  • 43.3% of TP53 mutations in pediatric low hypodiploid ALL were present in non-tumor cells, strongly suggesting inherited origin (Li-Fraumeni syndrome).
  • IKZF2 (HELIOS) deletions in 52.9% of low hypodiploid ALL; IKZF3 (AIOLOS) alterations in 13.2% of near haploid ALL.
  • RB1 alterations in 41.2% of low hypodiploid cases (P = 1.19 x 10^-5 vs near haploid).
  • CREBBP alterations in 32% of sequenced near haploid cases — the highest frequency at diagnosis reported in any ALL subtype.
  • Both subtypes exhibit activation of Ras and PI3K signaling (pERK, pmTOR, pS6 elevated).
  • PI3K inhibitor GDC-0941 and dual PI3K/mTOR inhibitor BEZ235 substantially inhibited proliferation of all hypodiploid ALL tumors tested ex vivo; MEK inhibitors were ineffective.
  • Gene expression profiling clearly distinguishes near haploid from low hypodiploid ALL (>15,000 differentially expressed probesets).

Genes & alterations

  • TP53: Missense, nonsense, and indel mutations in 91.2% of low hypodiploid ALL; many are known Li-Fraumeni mutations (e.g., p.Arg248Trp, p.Arg306*); 43.3% inherited.
  • NF1: Focal intragenic deletions (exons 15-35) and sequence mutations in 44.1% of near haploid ALL; biallelic in 76.7% due to aneuploidy; loss of GAP domain and NF1 protein expression.
  • NRAS: Activating mutations in near haploid ALL as part of RTK/Ras pathway; one inherited p.Gly12Ser variant identified.
  • KRAS: Activating mutations in near haploid ALL.
  • FLT3: Alterations in near haploid ALL targeting RTK signaling.
  • PTPN11: Activating mutations (e.g., p.Gly503Arg) in near haploid ALL; one case inherited (Noonan syndrome-associated).
  • IKZF2: Deletions in 52.9% of low hypodiploid ALL and 36.4% of adult low hypodiploid ALL; knockdown increases pERK/pS6, suggesting role as Ras/PI3K modulator.
  • IKZF3: Deletions and frame-shift mutations in 13.2% of near haploid ALL; knockdown increases pERK/pS6.
  • RB1: Alterations in 41.2% of low hypodiploid ALL; mutually exclusive with CDKN2A/CDKN2B loss.
  • CREBBP: Deletions and sequence mutations in 32% of sequenced near haploid cases, including HAT domain mutations.
  • EZH2: Three missense mutations with predicted deleterious effect identified.
  • MAPK1: Alterations in near haploid ALL as part of Ras pathway.
  • CDKN2A / CDKN2B: Deletions complementary to RB1 alterations in low hypodiploid ALL.
  • IKZF1: Infrequent in hypodiploid ALL, in contrast to non-hypodiploid high-risk B-ALL.

Clinical implications

  • Low hypodiploid ALL in children should prompt evaluation for Li-Fraumeni syndrome given 43.3% inherited TP53 mutation rate; family cancer history assessment is warranted.
  • PI3K and dual PI3K/mTOR inhibitors (GDC-0941, BEZ235) are potential therapeutic strategies for both near haploid and low hypodiploid ALL, as both subtypes show PI3K pathway dependence.
  • MEK inhibition alone is insufficient despite high Ras pathway mutation frequency — downstream PI3K pathway is the actionable node.
  • CREBBP mutations at diagnosis (unlike other ALL subtypes where they emerge at relapse) may have implications for treatment selection.

Limitations & open questions

  • Ex vivo drug sensitivity data from xenografts; in vivo and clinical trial validation of PI3K inhibitor efficacy is needed.
  • The genetic basis of aneuploidy in near haploid ALL (which lacks TP53 mutations) remains unknown.
  • Family cancer history was unavailable for most cases with inherited TP53 mutations.
  • The functional consequences of IKZF2/IKZF3 loss on Ras/PI3K modulation are preliminary (shRNA knockdown in cell lines).
  • Whether the high frequency of CREBBP mutations at diagnosis affects response to therapy (as relapse-associated CREBBP mutations do) is unresolved.

Citations from this paper used in the wiki

  • “Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%).”
  • “Low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%).”
  • “Almost half (43.3%) of the TP53 mutations in pediatric low hypodiploid ALL were present in non-tumor hematopoietic cells, suggestive of an inherited origin.”
  • “The PI3K- and dual PI3K/mTOR inhibitors substantially inhibited proliferation of all tumors examined.”
  • “Thirty of 68 near haploid cases (44.1%) had focal deletions or sequence mutations of NF1.”
  • “8 of 25 near haploid cases (32%) harboring a deletion or sequence mutation [of CREBBP]…this is the first ALL subtype found to have a high frequency of CREBBP mutations at diagnosis.”

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