PMID- 36251745
OWN - NLM
STAT- MEDLINE
DCOM- 20230214
LR  - 20230301
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 7
IP  - 2
DP  - 2023 Jan 24
TI  - Distinct clonal identities of B-ALLs arising after lenolidomide therapy for 
      multiple myeloma.
PG  - 236-245
LID - 10.1182/bloodadvances.2022007496 [doi]
AB  - Patients with multiple myeloma (MM) who are treated with lenalidomide rarely 
      develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and 
      biological relationship between these sequential malignancies is not yet clear. 
      We identified 17 patients with MM treated with lenalidomide, who subsequently 
      developed B-ALL. Patient samples were evaluated through sequencing, 
      cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) 
      staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were 
      assessed for shared mutations and recurrently mutated genes. Through whole exome 
      sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched 
      B-ALL), no mutational overlap between samples was observed. Unique dominant IgH 
      clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across 
      all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with 
      sufficient sequencing depth (>500x) revealed rare cells (average of 0.6% variant 
      allele frequency, or 1.2% of cells) with the same TP53 variant identified in the 
      subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL 
      samples shows that B-ALL developed as a second malignancy arising from a founding 
      population of cells that likely represented unrelated clonal hematopoiesis caused 
      by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a 
      common path for malignant transformation that may be similar to that of 
      TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells 
      containing TP53 variants in bone marrow at the initiation of lenalidomide 
      treatment suggests that cellular populations containing TP53 variants expand in 
      the presence of lenalidomide to increase the likelihood of B-ALL development.
CI  - (c) 2022 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Barnell, Erica K
AU  - Barnell EK
AUID- ORCID: 0000-0003-1631-1201
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Medicine, Washington University School of Medicine, St. Louis, MO.
FAU - Skidmore, Zachary L
AU  - Skidmore ZL
AUID- ORCID: 0000-0003-1928-7139
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Medicine, Washington University School of Medicine, St. Louis, MO.
FAU - Newcomer, Kenneth F
AU  - Newcomer KF
AUID- ORCID: 0000-0002-7034-498X
AD  - Department of Surgery, Washington University School of Medicine, St. Louis, MO.
FAU - Chavez, Monique
AU  - Chavez M
AUID- ORCID: 0000-0002-5317-3867
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
FAU - Campbell, Katie M
AU  - Campbell KM
AUID- ORCID: 0000-0001-6491-4432
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Medicine, Washington University School of Medicine, St. Louis, MO.
FAU - Cotto, Kelsy C
AU  - Cotto KC
AUID- ORCID: 0000-0003-0890-6889
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Medicine, Washington University School of Medicine, St. Louis, MO.
FAU - Spies, Nicholas C
AU  - Spies NC
AUID- ORCID: 0000-0002-5873-351X
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Ruzinova, Marianna B
AU  - Ruzinova MB
AUID- ORCID: 0000-0002-0833-8335
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Wang, Tianjiao
AU  - Wang T
AUID- ORCID: 0000-0002-8463-2720
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Abro, Brooj
AU  - Abro B
AUID- ORCID: 0000-0002-8047-1894
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Kreisel, Friederike
AU  - Kreisel F
AUID- ORCID: 0000-0002-7610-6480
AD  - Department of Pathology, Saint Louis University School of Medicine, St. Louis, 
      MO.
FAU - Parikh, Bijal A
AU  - Parikh BA
AUID- ORCID: 0000-0003-2490-8294
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Duncavage, Eric J
AU  - Duncavage EJ
AUID- ORCID: 0000-0003-4199-8906
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Frater, John L
AU  - Frater JL
AUID- ORCID: 0000-0002-4614-681X
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Lee, Yi-Shan
AU  - Lee YS
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Hassan, Anjum
AU  - Hassan A
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - King, Justin A
AU  - King JA
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
FAU - Kohnen, Daniel R
AU  - Kohnen DR
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
FAU - Fiala, Mark A
AU  - Fiala MA
AUID- ORCID: 0000-0002-0208-5023
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
FAU - Welch, John S
AU  - Welch JS
AUID- ORCID: 0000-0001-6656-3672
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
FAU - Uy, Geoffrey L
AU  - Uy GL
AUID- ORCID: 0000-0002-7809-0996
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
FAU - Vij, Kiran
AU  - Vij K
AUID- ORCID: 0000-0003-3633-0565
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO.
FAU - Vij, Ravi
AU  - Vij R
AUID- ORCID: 0000-0001-8795-3610
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
FAU - Griffith, Malachi
AU  - Griffith M
AUID- ORCID: 0000-0002-6388-446X
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
AD  - Department of Genetics, Washington University School of Medicine, St. Louis, MO.
FAU - Griffith, Obi L
AU  - Griffith OL
AUID- ORCID: 0000-0002-0843-4271
AD  - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
AD  - Department of Genetics, Washington University School of Medicine, St. Louis, MO.
FAU - Wartman, Lukas D
AU  - Wartman LD
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO.
AD  - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
AD  - Department of Pediatrics, Washington University School of Medicine, St. Louis, 
      MO.
LA  - eng
GR  - K22 CA188163/CA/NCI NIH HHS/United States
GR  - R00 HG007940/HG/NHGRI NIH HHS/United States
GR  - T32 CA009621/CA/NCI NIH HHS/United States
GR  - T32 HL007088/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Immunoglobulin Heavy Chains)
RN  - F0P408N6V4 (Lenalidomide)
SB  - IM
MH  - Humans
MH  - Bone Marrow/pathology
MH  - *Burkitt Lymphoma/pathology
MH  - Immunoglobulin Heavy Chains/genetics
MH  - In Situ Hybridization, Fluorescence
MH  - *Lenalidomide/adverse effects/therapeutic use
MH  - *Multiple Myeloma/drug therapy
MH  - Mutation
MH  - *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
PMC - PMC9860439
COIS- Conflicts-of-interest disclosure: These authors disclose the following: E.K.B. is 
      an owner, employee, and member of Geneoscopy Inc, and is an inventor of the 
      intellectual property owned by Geneoscopy Inc. The remaining authors disclose no 
      competing financial interests.
EDAT- 2022/10/18 06:00
MHDA- 2023/01/18 06:00
PMCR- 2022/10/21
CRDT- 2022/10/17 13:53
PHST- 2022/06/28 00:00 [accepted]
PHST- 2022/03/07 00:00 [received]
PHST- 2022/10/18 06:00 [pubmed]
PHST- 2023/01/18 06:00 [medline]
PHST- 2022/10/17 13:53 [entrez]
PHST- 2022/10/21 00:00 [pmc-release]
AID - 486813 [pii]
AID - 10.1182/bloodadvances.2022007496 [doi]
PST - ppublish
SO  - Blood Adv. 2023 Jan 24;7(2):236-245. doi: 10.1182/bloodadvances.2022007496.