BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: Frequency and clonal relationships

Jamshid S. Khorashad, Todd W. Kelley, Philippe Szankasi, Clinton C. Mason, Simona Soverini, Lauren T. Adrian, Christopher A. Eide, Matthew S. Zabriskie, Thoralf Lange, Johanna C. Estrada, Anthony D. Pomicter, Anna M. Eiring, Ira L. Kraft, David J. Anderson, Zhimin Gu, Mary Alikian, Alistair G. Reid, Letizia Foroni, David Marin, Brian DrukerThomas O'Hare, Michael W. Deininger

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (No 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.

Original languageEnglish (US)
Pages (from-to)489-498
Number of pages10
JournalBlood
Volume121
Issue number3
DOIs
StatePublished - Jan 17 2013

Fingerprint

Emitter coupled logic circuits
Protein-Tyrosine Kinases
Phosphotransferases
Mutation
Cloning
Missense Mutation
Clone Cells
Clonal Evolution
Mutation Rate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Organism Cloning

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Khorashad, J. S., Kelley, T. W., Szankasi, P., Mason, C. C., Soverini, S., Adrian, L. T., ... Deininger, M. W. (2013). BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: Frequency and clonal relationships. Blood, 121(3), 489-498. https://doi.org/10.1182/blood-2012-05-431379

BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML : Frequency and clonal relationships. / Khorashad, Jamshid S.; Kelley, Todd W.; Szankasi, Philippe; Mason, Clinton C.; Soverini, Simona; Adrian, Lauren T.; Eide, Christopher A.; Zabriskie, Matthew S.; Lange, Thoralf; Estrada, Johanna C.; Pomicter, Anthony D.; Eiring, Anna M.; Kraft, Ira L.; Anderson, David J.; Gu, Zhimin; Alikian, Mary; Reid, Alistair G.; Foroni, Letizia; Marin, David; Druker, Brian; O'Hare, Thomas; Deininger, Michael W.

In: Blood, Vol. 121, No. 3, 17.01.2013, p. 489-498.

Research output: Contribution to journalArticle

Khorashad, JS, Kelley, TW, Szankasi, P, Mason, CC, Soverini, S, Adrian, LT, Eide, CA, Zabriskie, MS, Lange, T, Estrada, JC, Pomicter, AD, Eiring, AM, Kraft, IL, Anderson, DJ, Gu, Z, Alikian, M, Reid, AG, Foroni, L, Marin, D, Druker, B, O'Hare, T & Deininger, MW 2013, 'BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: Frequency and clonal relationships', Blood, vol. 121, no. 3, pp. 489-498. https://doi.org/10.1182/blood-2012-05-431379
Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: Frequency and clonal relationships. Blood. 2013 Jan 17;121(3):489-498. https://doi.org/10.1182/blood-2012-05-431379
Khorashad, Jamshid S. ; Kelley, Todd W. ; Szankasi, Philippe ; Mason, Clinton C. ; Soverini, Simona ; Adrian, Lauren T. ; Eide, Christopher A. ; Zabriskie, Matthew S. ; Lange, Thoralf ; Estrada, Johanna C. ; Pomicter, Anthony D. ; Eiring, Anna M. ; Kraft, Ira L. ; Anderson, David J. ; Gu, Zhimin ; Alikian, Mary ; Reid, Alistair G. ; Foroni, Letizia ; Marin, David ; Druker, Brian ; O'Hare, Thomas ; Deininger, Michael W. / BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML : Frequency and clonal relationships. In: Blood. 2013 ; Vol. 121, No. 3. pp. 489-498.
@article{665e474dd1a84df9b4e3d751aac878b0,
title = "BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: Frequency and clonal relationships",
abstract = "BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (No 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70{\%} (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10{\%}), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.",
author = "Khorashad, {Jamshid S.} and Kelley, {Todd W.} and Philippe Szankasi and Mason, {Clinton C.} and Simona Soverini and Adrian, {Lauren T.} and Eide, {Christopher A.} and Zabriskie, {Matthew S.} and Thoralf Lange and Estrada, {Johanna C.} and Pomicter, {Anthony D.} and Eiring, {Anna M.} and Kraft, {Ira L.} and Anderson, {David J.} and Zhimin Gu and Mary Alikian and Reid, {Alistair G.} and Letizia Foroni and David Marin and Brian Druker and Thomas O'Hare and Deininger, {Michael W.}",
year = "2013",
month = "1",
day = "17",
doi = "10.1182/blood-2012-05-431379",
language = "English (US)",
volume = "121",
pages = "489--498",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "3",

}

TY - JOUR

T1 - BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML

T2 - Frequency and clonal relationships

AU - Khorashad, Jamshid S.

AU - Kelley, Todd W.

AU - Szankasi, Philippe

AU - Mason, Clinton C.

AU - Soverini, Simona

AU - Adrian, Lauren T.

AU - Eide, Christopher A.

AU - Zabriskie, Matthew S.

AU - Lange, Thoralf

AU - Estrada, Johanna C.

AU - Pomicter, Anthony D.

AU - Eiring, Anna M.

AU - Kraft, Ira L.

AU - Anderson, David J.

AU - Gu, Zhimin

AU - Alikian, Mary

AU - Reid, Alistair G.

AU - Foroni, Letizia

AU - Marin, David

AU - Druker, Brian

AU - O'Hare, Thomas

AU - Deininger, Michael W.

PY - 2013/1/17

Y1 - 2013/1/17

N2 - BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (No 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.

AB - BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (No 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.

UR - http://www.scopus.com/inward/record.url?scp=84872462658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872462658&partnerID=8YFLogxK

U2 - 10.1182/blood-2012-05-431379

DO - 10.1182/blood-2012-05-431379

M3 - Article

C2 - 23223358

AN - SCOPUS:84872462658

VL - 121

SP - 489

EP - 498

JO - Blood

JF - Blood

SN - 0006-4971

IS - 3

ER -