The landscape of somatic mutations in Infant MLL rearranged acute lymphoblastic leukemias

Authors

Andersson AK

Ma J

Wang J

Chen X

Gedman AL

Dang J

Nakitandwe J

Holmfeldt L

Parker M

Easton J

Huether R

Kriwacki R

Wu G

Li Y

Mulder H

Raimondi S

Pounds S

Kang G

Shi L

Becksfort J

Gupta P

Payne-Turner D

Vadodaria B

Boggs K

Yergeau D

Manne J

Song G

Edmonson M

Nagahawatte M

Wei L

Cheng C

Pei D

Sutton R

Venn NC

Chetcuti A

Rush A

Catchpoole D

Heldrup J

Fioretos T

Lu C

Ding L

Pui CH

Shurtleff S

Mullighan CG

Mardis ER

Wilson RK

Gruber TA

Zhang J

Downing JR

Doi

10.1038/ng.3230

PMID: 25730765 · DOI: 10.1038/ng.3230 · Journal: Nat Genet (2015)

TL;DR

This study defines the mutational landscape of infant MLL-rearranged (MLL-R) acute lymphoblastic leukemia (ALL) through comprehensive sequencing of 65 infants and 20 older children. Infant MLL-R ALL exhibits one of the lowest somatic mutation frequencies in human cancer, averaging only 1.3 non-silent mutations per case. Despite this paucity, 47% of cases harbor activating mutations in kinase/PI3K/RAS signaling pathways, which are frequently sub-clonal and lost at relapse. In contrast, older children with MLL-R leukemia have significantly higher mutation burdens and frequent alterations in epigenetic regulators.

Cohort & data

Key findings

  • Extremely Low Mutation Burden: Infant MLL-rearranged (MLL-R) ALL has an exceedingly low somatic mutation rate, with an average of 1.3 non-silent mutations per case in the predominant leukemic clone.
  • Kinase/PI3K/RAS Signaling: Activating mutations in kinase/PI3K/RAS pathways were identified in 47% of infant MLL-R cases. These include mutations in FLT3 (19%), KRAS (15%), and NRAS (13%).
  • Sub-clonality and Relapse: Many signaling pathway mutations were sub-clonal and frequently lost at relapse, suggesting they may not be essential for leukemic maintenance or that conventional treatments fail to eliminate the founder clone.
  • Comparison to Older Children: MLL-R leukemia in older children had a significantly higher mutation burden (mean 6.5 vs 1.3 non-silent mutations, P=7.15×10⁻⁵) and frequent mutations in epigenetic regulators (45%), which were rare in infants.

Genes & alterations

  • KMT2A (MLL): Rearrangements are the primary driver; 11q23 translocations were present in 47 infants.
  • FLT3: Activating mutations found in 19% of infant MLL-R cases; often sub-clonal.
  • KRAS & NRAS: Activating mutations in RAS pathway found in ~28% of cases combined.
  • CREBBP: Mutations identified in relapse samples, consistent with roles in treatment resistance.
  • NT5C2: Relapse-associated mutations identified in infant ALL.
  • TP53: Rare mutations observed, consistent with the low overall mutation burden.

Clinical implications

  • Prognostic Marker: Kinase/PI3K/RAS pathway mutations showed a trend toward poorer Event-Free Survival (EFS) and Overall Survival (OS), though the cohort size limited statistical significance for independent prediction.
  • Treatment Resistance: The loss of signaling mutations at relapse suggests that the founder clone persists through standard therapy, highlighting the need for treatments targeting the MLL fusion or its downstream effectors.
  • Biomarker Potential: The paucity of secondary mutations suggests that the KMT2A rearrangement itself is a potent driver, potentially simplifying the search for therapeutic targets but complicating the use of secondary mutations as reliable clinical biomarkers.

Limitations & open questions

  • Small Relapse Cohort: Only seven matched diagnostic/relapse infant MLL-R samples were analyzed, limiting the understanding of clonal evolution.
  • Functional Impact: While kinase/PI3K/RAS mutations are activating, their sub-clonal nature raises questions about their necessity for leukemogenesis versus promoting clonal expansion.
  • Non-MLL-R Comparison: The study also included 18 non-MLL-R infants, but the primary focus was on the MLL-R landscape.

Citations from this paper used in the wiki

  • “Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis.” PMID:25730765
  • “Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations.” PMID:25730765
  • “Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%.” PMID:25730765

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