* INCLUSION CRITERIA:
* Affected participants (Recipients)
* History of deleterious or suspected deleterious (defined as P/LP or VUS with RUNX1 phenotype) germline RUNX1 mutation as defined by ClinVar (nih.gov)
* Histological confirmation of a myeloid malignancy - acute or chronic leukemia (\<5% marrow blasts preferred) or myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) (\<10% marrow blasts preferred). Participants may be treated on this study to achieve preferred blast cutoffs. Participants with poorly responsive or relapsed disease remain eligible and may proceed as the graft-versus-leukemia (GVL) effect may produce cures.
Subjects requiring standard therapies to prepare for HCT should ideally be referred to this study in remission, if possible. However, sometimes disease status changes during evaluation for HCT and it is necessary to establish disease control through the administration of standard therapies during evaluation for HCT. If ongoing therapy for the underlying disease outside of the NIH is not in the best interest of the subject according to the clinical judgment of the NIH PI, then the subject may receive standard treatment for his/her underlying hematologic malignancy as a bridge to HCT on this protocol, prior to starting the research phase of the study. If it becomes apparent that the subject will not be able to proceed to HCT, then he/she must come off study. Subjects receiving standard therapy will be told about the therapy, associated risks, potential benefits, alternatives to the proposed therapy, and the availability of receiving the same treatment elsewhere, outside of a research protocol.
* Availability of a haploidentical donor (HLA-match only).
* Age \>= 4 and \<= 70 years
* Karnofsky (\>=16 years) or Lansky (\<16 years) \>=60%
* For human immunodeficiency virus (HIV)-infected participants, participant must be on effective anti-retroviral therapy, without uncontrolled opportunistic infection and have approval via Transplant Infectious Disease consultation. Consider donor with CCR5(delta)32 homozygosity for these participants.
* For individuals with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load (VL) must be undetectable on suppressive therapy, if indicated.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV VL.
* Contraception as follows:
---Women of child-bearing potential (WOCBP) must agree to use highly effective contraception (hormonal, intrauterine device \[IUD\], abstinence, surgical sterilization) at the study entry and up to and 12 months post conditioning and/or post-transplant.
* Men that can father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 12 months posttransplant or 4 months after conditioning if transplant is not done. We also will recommend men that can father children with partners that can bear children ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Men that can father children must not freeze or donate sperm within the same period.
* Breastfeeding participants must be willing to discontinue breastfeeding during the study and for 12 months post-transplant or 1 week after conditioning if transplant is not done.
* Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (30 minutes drive), for a minimum of 100 days after transplant or longer if there are complications. The participants must commit to having an adult caregiver with them during the first 100 days after the transplant
* Participants or parent/guardian/legally authorized representative must be able to understand and willing to sign a written informed consent document.
* Additional criteria for recipients suitable for MAC
* Age \<= 65 years
* HCT-CI \<4
* Pulmonary function tests (PFTs): Forced expiratory volume in the first second (FEV1) and adjusted diffusion capacity of carbon monoxide (DLCO) \>=66%, without dyspnea at rest or oxygen requirement. If too young to cooperate with PFTs, must have \>=92% oxygen saturation on room air and no dyspnea at rest.
* Left ventricular ejection fraction (LVEF) \>=50% by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan (101)
* Recipients must have adequate organ function as defined below:
* Total bilirubin \<1.5 x institutional upper limit of normal (iULN) (unless Gilbert disease, hemolysis)
* Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) \<=2.5 x iULN (unless therapy related and will improve in discussion with the National Institute of Diabetes and Digestive and Kidney Diseases \[NIDDK\])
* Creatinine within normal institutional limits or 24-hour urine or calculated creatinine clearance \>=60 mL/min/1.73 m\^2 for individuals with creatinine levels above institutional normal (calculated using the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation)
* Additional criteria for recipients suitable for RIC
* Age \<=70 years
* PFTs: FEV1 and DLCO \>=50%, without dyspnea at rest or oxygen requirement. If too young to cooperate with PFTs, must have \>=92% oxygen saturation on room air and no dyspnea at rest
* LVEF \>=40% by ECHO or MUGA obtained within 2 months of HSCT (Children s Oncology Group \[COG\] criteria).
* Recipients must have adequate organ function as defined below:
* Total bilirubin \<2.5 x iULN (unless Gilbert disease, hemolysis)
* AST/ALT \<3.5 x iULN (unless therapy related and will improve in discussion with NIDDK)
* Creatinine within normal institutional limits or 24-hour urine or calculated creatinine clearance \>=50 mL/min/1.73 m\^2 for individuals with creatinine levels above institutional normal (calculated using the CKD-EPI equation)
* Unaffected participants
* Haploidentical donors
----Age \>=4 years
* Participants or parent/guardian must be able to understand and willing to sign a written informed consent document.
* Unaffected family members
* Age \>=18 years
* If the participant is a blood relative of the recipient, participant must be negative for RUNX1 mutations by molecular testing
* Participants must be able to understand and willing to sign a written informed consent document.
EXCLUSION CRITERIA:
-All participants
* Recipients who are receiving any investigational agent except virus specific T cells (VST)
* Active non-hematologic malignancies
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the drugs used in study.
* Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (except atrial fibrillation if cleared by cardiology consultation)
* Participants without access to medical care at home.
* Positive serum or urine beta-human chorionic gonadotropin (beta-hCG) test at screening
* Uncontrolled intercurrent illness evaluated by history, physical exam, and laboratory studies or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
