Changes

''MDS/AML''

''MDS/AML''

GATA2 overexpression has been reported in up to half of non-familial AML and correlates with poor prognosis with shorter overall and event-free survival when treated with standard chemotherapy [6,7]. Bone marrow biopsies are frequently hypocellular in contrast to the common MDS marrow picture, with abundant atypical megakaryocytes in >90% of patients [8].  

GATA2 overexpression has been reported in up to half of non-familial AML and correlates with poor prognosis with shorter overall and event-free survival when treated with standard chemotherapy [6,7]. Bone marrow biopsies are frequently hypocellular in contrast to the common MDS marrow picture, with abundant atypical megakaryocytes in >90% of patients [8].  

AML with inv(3)(q21;3q26.2)/t(3;3)(q21.3;q26.2) accounts for 1-2% of all AML [9]. It is an aggressive disease with short survival [9]. It is associated with aberrant expression of the stem-cell regulator EVI1 [9]. Both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, identified as the cause of sporadic familial AML/MDS (and MonoMac/Emberger syndromes) [9].

AML with inv(3)(q21;3q26.2)/t(3;3)(q21.3;q26.2) accounts for 1-2% of all AML [9]. It is an aggressive disease with short survival [9]. It is associated with aberrant expression of the stem-cell regulator EVI1 [9]. Both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, identified as the cause of sporadic familial AML/MDS (and MonoMac/Emberger syndromes) [9].

''CML''

''CML''

GATA2 mutation Leu359Val (NM_001145661.1:c.1075T>G) gain-of-function has been found in approximately 10% of patients with accelerated or blast phase CML but not chronic lymphocytic leukemia (CLL) or acute lymphoblastic leukemia (ALL) [10,11]. This is thought to be mediated through PU.1 inhibition [2]. While GATA2 overexpression has been associated with AML, and Leu359Val gain-of-function mutation with CML, loss-of-function mutations of GATA2 such as Thr354Met (NM_001145661.1:c.1061C>T) have been linked to MDS [2]. Leu359 and Thr354 are located in the same region on the second zinc finger of GATA2, highlighting the influence of GATA2 in myeloid precursors [2].

GATA2 mutation Leu359Val (NM_001145661.1:c.1075T>G) gain-of-function has been found in approximately 10% of patients with accelerated or blast phase CML but not chronic lymphocytic leukemia (CLL) or acute lymphoblastic leukemia (ALL) [10,11]. This is thought to be mediated through PU.1 inhibition [2]. While GATA2 overexpression has been associated with AML, and Leu359Val gain-of-function mutation with CML, loss-of-function mutations of GATA2 such as Thr354Met (NM_001145661.1:c.1061C>T) have been linked to MDS [2]. Leu359 and Thr354 are located in the same region on the second zinc finger of GATA2, highlighting the influence of GATA2 in myeloid precursors [2].

   

   

''Non-small cell lung cancer (NSCLC)''

''Non-small cell lung cancer (NSCLC)''

The GATA2 transcriptional network is a requisite for RAS oncogene-driven NSCLC [12]. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected [12]. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development [12]. Furthermore, Gata2 deletion in established Kras-mutant tumors has been found to induce significant regression [12].

The GATA2 transcriptional network is a requisite for RAS oncogene-driven NSCLC [12]. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected [12]. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development [12]. Furthermore, Gata2 deletion in established Kras-mutant tumors has been found to induce significant regression [12].