Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome

Asou, Hiroya; Matsui, Hirotaka; Ozaki, Yuko; Nagamachi, Akiko; Nakamura, Megumi; Aki, Daisuke; Inaba, Toshiya

doi:10.1016/j.bbrc.2009.04.004

Cited by 68 publications

(76 citation statements)

References 14 publications

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“…18 Three commonly deleted regions in 7q have been identified, including commonly deleted region 1 (7q21-22), commonly deleted region 2 (7q34) and commonly deleted region 3 (7q35-36). 11,[19][20][21][22][23] Several genes on 7q have been considered as potential tumor suppressor genes and the loss of one or more of these genes could lead to development of a malignant myeloid neoplasm. SAMD9L, located on 7q21.3, plays a role in ERK signal transduction and haploinsufficiency of SAMD9L can result in sustained ERK activation and prolonged cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…Of the remaining 27 patients, blasts were not increased and criteria for therapy-related myeloid neoplasms were not met in the diagnostic bone marrow sample at the time of del(7q) identification. This group included 10 patients (cases [13][14][15][19][20][21][22][23][24][25] with mild dysplasia, 16 patients (cases 16-18, 26-38) who did not have dysplasia and 1 patient in whom morphological assessment was difficult due to significant involvement by lymphoma (case 39) (Figure 1).…”

Section: Bone Marrow and Peripheral Blood Findingsmentioning

confidence: 99%

“…Of the 10 patients with mild dyspoiesis, 7 (patients 15,[19][20][21][22][23][24] showed a variable degree of cytopenia and 3 (patients 13, 14, 25) had normal complete blood cell counts. Of the 16 patients who showed no evidence of dysplasia, 6 (cases [16][17][18][26][27][28] demonstrated mild cytopenia and the other 10 patients (cases 29-38) had normal complete blood cell counts (Figure 1).…”

Section: Bone Marrow and Peripheral Blood Findingsmentioning

confidence: 99%

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Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

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Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median followup of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding. Abnormalities of chromosome 7, either monosomy (−7) or deletion of the long arm (del(7q)), are the most common cytogenetic abnormalities detected in acute myeloid leukemia and myelodysplastic syndromes. 1-3 Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively. 6 Therapy-related myeloid neoplasm is a late complication of cytotoxic therapies for primary malignant and non-malignant diseases. Cytogenetic abnormalities can be detected in more than 90% of patients with therapy-related myeloid neoplasms, and more than half of these patients have a complex karyotype. 7 Del(7q)/ − 7 presents in~50% of patients with therapy-related myeloid neoplasms and are often associated with prior exposure to alkylating agents or ionizing radiation. 1,[8][9][10][11][12][13] Any newly emerged cytogenetic abnormalities in patients with a prior history of cytotoxic therapies often raises the concern of development of therapy-related myeloid neoplasms, especially when the abnormalities include del(7q)/ − 7.In our practice, we have observed that some patients develop isolated del(7q) in their bone marrow following cytotoxic therapies, yet never develop therapy-related myeloid neoplasms with close follow-up. In order to better understand the

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Section: Discussionmentioning

confidence: 99%

Section: Bone Marrow and Peripheral Blood Findingsmentioning

confidence: 99%

Section: Bone Marrow and Peripheral Blood Findingsmentioning

confidence: 99%

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Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

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“…Little is known about the biological roles of SAMD9L. Interestingly, SAMD9L and its paralog gene, SAMD9, exist in a short fragment of the human chromosome 7q21 region that is commonly deleted in patients with myeloid leukemia and myelodysplastic syndrome (Asou et al 2009). SAMD9L is expressed at significantly lower levels in breast carcinomas relative to normal breast epithelia from the same patients (Li et al 2007).…”

Section: Discussionmentioning

confidence: 99%

ΔNp63α represses anti-proliferative genes via H2A.Z deposition

et al. 2012

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DNp63a is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because DNp63a and p53 bind virtually identical DNA sequence motifs, it has been proposed that DNp63a functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress DNp63a and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by DNp63a that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of DNp63a status but fails to transactivate genes repressed by DNp63a. We found that DNp63a associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of DNp63a-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by DNp63a and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by DNp63a knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of DNp63a.

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“…The observation that MLL3, a related gene located at chromosome band 7q34, is mutated in some human cancers raises the possibility that haploinsufficiency for MLL5 and MLL3 may interact in leukemogenesis. [42][43][44] A microdeletion located on chromosome band 7q21.3 that was recently implicated as containing a haploinsufficient myeloid TSG 45 might also cooperate with deletion of the 7q22 CDS. The idea that multiple 7q genes might contribute to leukemogenesis is consistent with recent studies of myeloid malignancies with 5q deletions, which suggest that haploinsufficiency for CTNNA1, APC, EGR1, RPS14, miR-145, and miR-146a cooperate to deregulate hematopoietic growth.…”

Section: Discussionmentioning

confidence: 99%

Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies

Wong¹,

Zhang

Lieuw

et al. 2010

Blood

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Monosomy 7 and del(7q) are associated with adverse features in myeloid malignancies. A 2.5-Mb commonly deleted segment (CDS) of chromosome band 7q22 is implicated as harboring a myeloid tumor suppressor gene (TSG); however, molecular analysis of candidate TSGs has not uncovered loss of function. To determine whether haploinsufficiency for the 7q22 CDS contributes to myeloid leukemogenesis, we performed sequential gene targeting to flank a region of orthologous synteny on mouse chromosome band 5A3 with loxP sites. We then generated Mx1-Cre, 5A3 fl mutant mice and deleted the targeted interval in vivo. Although excision was inefficient, we confirmed somatic deletion of the 5A3 CDS in the hematopoietic stem cell compartment. Mx1-Cre, 5A3 fl mice show normal hematologic parameters and do not spontaneously develop myeloid malignancies. The 5A3 fl deletion does not cooperate with oncogenic Kras G12D expression, Nf1 inactivation, or retroviral mutagenesis to accelerate leukemia development and did not modulate responsiveness to antileukemia drugs. These studies demonstrate that it is feasible to somatically delete a large chromosomal segment implicated in tumor suppression in hematopoietic cell populations in vivo; however, our data do not support the hypothesis that the 7q22/5A3 CDS interval contains a myeloid TSG. IntroductionLoss of chromosome 7 and deletion of a segment of the long arm (monosomy 7 and del(7q)) are recurring cytogenetic abnormalities in de novo and therapy-induced myeloid malignancies that are associated with advanced age, antecedent myelodysplastic syndrome (MDS), and resistance to current treatments. 1 Based on precedents in other cancers, it is likely that loss of one or more 7q tumor suppressor genes (TSGs) contributes to leukemogenesis. To facilitate the identification of candidate myeloid TSGs, Le Beau et al delineated 2 commonly deleted segments (CDSs) in patients with myeloid disorders characterized by a del(7q), a proximal interval within band q22 that accounts for most cases, and a second CDS in bands q32-34. 2 Using an ordered set of yeast artificial chromosome clones as probes, these investigators then performed fluorescence in situ hybridization (FISH) experiments to further characterize leukemias with deletion breakpoints within 7q22 and implicated an approximately 2.5-Mb CDS as harboring a myeloid TSG. We and others have extensively characterized this CDS, identified and cloned multiple genes from the interval, analyzed leukemia samples for mutations in these candidate TSGs, and performed Taqman real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays to measure expression levels in normal and leukemic human bone marrows. [3][4][5][6] These studies did not uncover biallelic inactivation or epigenetic silencing of any candidate TSGs located within this CDS. [3][4][5] Thus, it was hypothesized that inactivation of a single allele (haploinsufficiency) of one or more TSGs located within the 2.5-Mb CDS might contribute to leukemogenesis. 4,5 Recent technical ...

show abstract

Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome

Cited by 68 publications

References 14 publications

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

ΔNp63α represses anti-proliferative genes via H2A.Z deposition

Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies

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