PMID- 9226152
OWN - NLM
STAT- MEDLINE
DCOM- 19970807
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 90
IP  - 2
DP  - 1997 Jul 15
TI  - All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have 
      treatment-related hematologic disorders.
PG  - 535-41
AB  - The involvement of 11q23-balanced translocations in acute leukemia after 
      treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) 
      is being recognized with increasing frequency. We and others have shown that the 
      gene at 11q23 that is involved in all of these treatment-related leukemias is MLL 
      (also called ALL1, Htrx, and HRX). In general, the translocations in these 
      leukemias are the same as those occurring in de novo leukemia [eg, t(9;11), 
      t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no 
      more than 5% to 10% of any particular translocation type. We have cloned the 
      t(11;16)(q23;p13.3) and have shown that it involves MLL and CBP (CREB binding 
      protein). The CBP gene was recently identified as a partner gene in the t(8;16) 
      that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in 
      treatment-related acute myeloid leukemia. We have studied eight t(11;16) 
      patients, all of whom had prior therapy with drugs targetting topo II with 
      fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid 
      contig covering the CBP gene. Both probes were split in all eight patients and 
      the two derivative (der) chromosomes were each labeled with both probes. Use of 
      an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one 
      patient revealed some variability in the breakpoint because it was on the der(16) 
      in three patients, on the der(11) in another, and split in four others. We assume 
      that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual 
      because three of them presented with a myelodysplastic syndrome (MDS) most 
      similar to chronic myelomonocytic leukemia (CMMoL) and one other had 
      dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or 
      with t-AML. Using FISH and these same probes to analyze the lineage of bone 
      marrow cells from one patient with CMMoL, we showed that all the mature monocytes 
      contained the fusion genes as did some of the granulocytes and erythroblasts; 
      none of the lymphocytes contained the fusion gene. The function of MLL is not 
      well understood, but many domains could target the MLL protein to particular 
      chromatin complexes. CBP is an adapter protein that is involved in regulating 
      transcription. It is also involved in histone acetylation, which is thought to 
      contribute to an increased level of gene expression. The fusion gene could alter 
      the CBP protein such that it is constitutively active; alternatively, it could 
      modify the chromatin-association functions of MLL.
FAU - Rowley, J D
AU  - Rowley JD
AD  - Department of Medicine, University of Chicago Medical Center, IL 60637-1470, USA.
FAU - Reshmi, S
AU  - Reshmi S
FAU - Sobulo, O
AU  - Sobulo O
FAU - Musvee, T
AU  - Musvee T
FAU - Anastasi, J
AU  - Anastasi J
FAU - Raimondi, S
AU  - Raimondi S
FAU - Schneider, N R
AU  - Schneider NR
FAU - Barredo, J C
AU  - Barredo JC
FAU - Cantu, E S
AU  - Cantu ES
FAU - Schlegelberger, B
AU  - Schlegelberger B
FAU - Behm, F
AU  - Behm F
FAU - Doggett, N A
AU  - Doggett NA
FAU - Borrow, J
AU  - Borrow J
FAU - Zeleznik-Le, N
AU  - Zeleznik-Le N
LA  - eng
GR  - CA42557/CA/NCI NIH HHS/United States
GR  - CA72734/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (KMT2A protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Topoisomerase II Inhibitors)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.3.1.48 (CREBBP protein, human)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Antineoplastic Agents/*adverse effects
MH  - CREB-Binding Protein
MH  - Child
MH  - Child, Preschool
MH  - Chromosome Mapping
MH  - *Chromosomes, Human, Pair 11
MH  - *Chromosomes, Human, Pair 16
MH  - DNA-Binding Proteins/*genetics
MH  - Female
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Leukemia/chemically induced/*drug therapy/*genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - Myelodysplastic Syndromes/chemically induced/*genetics/pathology
MH  - Myeloid-Lymphoid Leukemia Protein
MH  - Neoplasms/*drug therapy/radiotherapy
MH  - Neoplasms, Second Primary/chemically induced/*genetics
MH  - Nuclear Proteins/*genetics
MH  - *Proto-Oncogenes
MH  - Topoisomerase II Inhibitors
MH  - *Trans-Activators
MH  - Transcription Factors/*genetics
MH  - *Translocation, Genetic
MH  - Zinc Fingers
EDAT- 1997/07/15 00:00
MHDA- 1997/07/15 00:01
CRDT- 1997/07/15 00:00
PHST- 1997/07/15 00:00 [pubmed]
PHST- 1997/07/15 00:01 [medline]
PHST- 1997/07/15 00:00 [entrez]
AID - S0006-4971(20)58926-X [pii]
PST - ppublish
SO  - Blood. 1997 Jul 15;90(2):535-41.